Role of Interleukin-31 and Oncostatin M in Itch and Neuroimmune Communication

Ferda Cevikbas; Cordula Kempkes; Timo Buhl; Christian Mess; Joerg Buddenkotte; Martin Steinhoff

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Carstens E, Akiyama T, editors. Itch: Mechanisms and Treatment. Boca Raton (FL): CRC Press/Taylor & Francis; 2014.

Itch: Mechanisms and Treatment.

Show details

Contents

< Prev Next >

Chapter 13Role of Interleukin-31 and Oncostatin M in Itch and Neuroimmune Communication

Ferda Cevikbas, Cordula Kempkes, Timo Buhl, Christian Mess, Joerg Buddenkotte, and Martin Steinhoff.

13.1. INTRODUCTION

13.1.1. Skin as a Neuroimmune Organ

Generally, cytokines comprise a large family of secreted proteins regulating a variety of cellular functions during inflammation and immune responses. Cytokines activate immune as well as resident skin cells including keratinocytes, endothelial cells, Langerhans cells, mast cells, or fibroblasts. Subsequently, those cells release mediators that potentially communicate with sensory nerves regulating neurogenic inflammation, pain, or itch (Chung et al. 2003, 2004; Dallos et al. 2006; E et al. 2006; Grewe et al. 2000; Huang et al. 2008; Ibrahim et al. 2005; Kakurai et al. 2001; Raychaudhuri et al. 2008; Tanaka et al. 2007). In addition, immune cells (e.g., mast cells) can directly communicate with sensory nerves during inflammation and pruritus (Roosterman et al. 2006) via histamine, tryptase, prostanoids, or RL-peptides (Steinhoff et al. 2000). For example, mediators like histamine or tryptase released by mast cells during inflammation and allergic reactions can directly “talk” to sensory nerves (Steinhoff et al. 2000, 2003) and are thus targets for therapy.

In recent years, new evidence indicates that cytokines or chemokines can also directly communicate with sensory nerves via activation of high-affinity cytokine or chemokine receptors that are involved in pain or inflammation including IL-1, IL-8, IL-10, MCP, CCL2, CCL4, CCL5, MIP1α, for example (Liou et al. 2012, 2013; Liu et al. 2013; Saika et al. 2012; Zhang et al. 2012). Although of importance, information about how immune cells—especially T cells—directly communicate with nerves to regulate neurogenic inflammation, pain, and pruritus is very limited (Bonness and Bieber 2007; Hanifin 2009; Ishiuji et al. 2008; Ong and Leung 2006; Sehra et al. 2008; Yosipovitch et al. 2003; Yosipovitch and Papoiu 2008). Recent studies showed that IL-31, a newly discovered cytokine (Bilsborough et al. 2006; Dillon et al. 2004), and its related cytokine OSM, two members of the IL-6 family of cytokines (Bando et al. 2006; Bilsborough et al. 2006; Boniface et al. 2007; Drogemuller et al. 2008; Grimstad et al. 2009; Morikawa et al. 2004; Neis et al. 2006; Sonkoly et al. 2006; Tamura et al. 2003), are good candidates to understand the role of T-cell-induced neuronal communication. Interestingly, the expression of IL-6 receptor on neurons was described in rats by immunohistochemistry many years ago, although a functional role for IL-6 and its members in sensory nerves is still lacking (Grothe et al. 2000).

13.1.2. IL-6 Family of Cytokines

The IL-6 family of cytokines is comprised of IL-6, IL-21, IL-31, OSM, CNTF, and neuropoietin. OSM (Zhang et al. 2008), as well as “neurotrophic cytokines” such as BDNF (CNTF) or neuropoietin (Bando et al. 2006) have been shown to be important for neuronal regulation. The gp130/IL-6 cytokine family is involved in various important physiological and pathophysiological processes like nerve growth, inflammation, and immune defense (Bando et al. 2006). A role of IL-31 is thus far best understood for its role in atopic diseases and itch.

13.1.2.1. IL-31

The gene encoding human IL-31 is located on chromosome 12q24.31 and the mouse ortholog is situated in a synthetic region of chromosome 5. The IL-31 cDNA is composed of an open reading frame encoding a 164 amino acid (aa) precursor and a predicted 141 aa mature polypeptide containing the four α-helix structure (Steinhoff et al. 2010). In mice, IL-31 mRNA is predominantly released by CD4⁺ TH2 helper cells, anti-CD3/CD28-stimulated TH1 and TH2 cells, albeit in CD4⁺ TH2 cells with significant higher levels (Dillon et al. 2004). In humans, IL-31 mRNA and protein is predominantly expressed and released by CLA⁺(skin-homing⁺)-CD45RO⁺ memory T cells, and increased expression was found in atopic dermatitis patients (Bilsborough et al. 2006; Dillon et al. 2004). Activated Th2 cells are the main source of IL-31 in humans and mice (Dillon et al. 2004; Sonkoly et al. 2006). Our own and recent studies showed that besides other tissues, IL-31 RNA and protein is also strongly expressed in murine skin and not in DRG neurons (Dillon et al. 2004; Sonkoly et al. 2006). In humans, IL-31 has been detected mainly in different immune cells in the skin. Intriguingly, IFNγ is able to induce the production of IL-31 in human microvascular endothelial cells (Feld et al. 2010). In human mast cells, antimicrobial peptides cathelicidin and β-defensin were reported to affect the IL-31 production, suggesting that IL-31 might derive from different dermal skin types triggered by other cytokines or peptides.

IL-31 seems to be an important cytokine, transmitting itch to the central nervous system. In a murine model, overexpression of IL-31 leads to an atopic dermatitis-like phenotype, including high itch rate, skin lesion formation, increased transepidermal water loss and dry, scaly skin (Dillon et al. 2004). This is of translational value, as patients with atopic dermatitis present high expression of IL-31 in the skin (Nobbe et al. 2012).

13.1.2.2. OSM

OSM has been identified to be significantly involved in several critical physiological and pathophysiological processes, such as inflammation, autoimmunity, tissue remodeling, and cancer (Silver and Hunter 2010). In different murine models, OSM was capable of stimulating collagen production and proliferation of lung and dermal fibroblasts, and OSM overexpression resulted in eosinophilia, lung fibrosis, and lymphocytic infiltration (Bamber et al. 1998; Duncan et al. 1995; Langdon et al. 2000). In patients with rheumatoid arthritis (one of the textbook-classic diseases for Th1-dominated immune dysregulation), OSM is expressed in the synovial fluid and stimulates synovial fibroblasts to proliferate and produce IL-6, MCP-1, and the chemokine CCL13, which contributes to attraction of inflammatory cells (Hintzen et al. 2009; Hui et al. 1997; Ihn and Tamaki 2000). Other studies support relevant involvement of OSM in hematopoiesis (Miyajima et al. 2000; Mukouyama et al. 1998) and hepatocyte differentiation (Kamiya et al. 1999; Miyajima et al. 2000). Interestingly, OSM was also found to have tumor-protective capabilities because OSM can block proliferation in several cancer cell lines, and disease progress in some cancer patients was connected with loss of responsiveness to OSM (Lacreusette et al. 2007; Ouyang et al. 2006). OSM mRNA has been detected in various human tissues and cells, especially in T cells, neutrophils and eosinophils, DRGs, and spinal cord neurons, as well as microglia cells within the central nervous system (Repovic and Benveniste 2002; Tamura et al. 2002). Recent studies also showed that OSM secreted by skin infiltrating T cells is involved in skin inflammation and induce heat hypersensitivity in TRPV1+ neurons (Boniface et al. 2007; Langeslag et al. 2011).

13.1.2.3. Ciliary Neurotrophic Factor

Ciliary neurotrophic factor (CNTF) is produced by astrocytes, Schwann cells, and T cells (Jones et al. 2010; Sleeman et al. 2000; Stockli et al. 1991). It binds to the CNTF receptor α (CNTFRα), triggering a heterodimerization of gp130 and leukemia inhibitory factor receptor (LIFR) (Matthews and Febbraio 2008) with downstream signaling through the JAK/STAT pathway (Davis et al. 1991). The expression of the α receptor is mainly found in cells of the central and peripheral nervous system, and in cells of peripheral tissues such as muscle cells and adipocytes (Davis et al. 1991; Matthews and Febbraio 2008; Sleeman et al. 2000). This broad spectrum of receptor expression reflects the function of CNTF as a modulator of neuronal differentiation (Freda et al. 1990; Vlotides et al. 2004), inhibitor of neurodegeneration (Sendtner et al. 1992), myothrophic effector (Guillet et al. 1999; Helgren et al. 1994), mediator of weight loss (Ettinger et al. 2003; Henderson et al. 1994; Kokoeva et al. 2005), and insulin sensitivity (Matthews and Febbraio 2008; Sleeman et al. 2003). CNTF overexpression is shown to induce increased sensory innervation of the skin (LeMaster et al. 1999).

13.1.2.4. Neuropoietin

The latest member of the IL-6 related cytokine family, the CNTFRα ligand neuropoietin (NP) was identified by a computational analysis screen effort in 2004 (Derouet et al. 2004). The cloning paper describes high NP expression in the neuroepithelium during developmental stages of the mouse embryo when CNTF is absent while postnatal production of the protein is not detectable. This observation implicates an important role for NP during nervous system development. Subsequent studies link NP to the regulation of murine neuronal differentiation (Ohno et al. 2006), adipogenesis (Derouet et al. 2004), and bone formation (McGregor et al. 2010). In humans, neuropoietin so far appears to be without relevance because, although an NP ortholog is found, all sequenced individuals (n = 93) reveal an 8-nt deletion, suggesting NP to be a pseudogene in the human genome.

All together, the IL-6 cytokine family including IL-31 and OSM may be important neuroimmune mediators in the skin regulating inflammation, itch, and probably pain. A role of this cytokine family in cell growth processes has also been verified (Betz et al. 1998; Yoshida et al. 1996). Regarding inflammatory skin diseases and cutaneous tumors, IL-31 has been demonstrated to be involved in atopic dermatitis (AD), pruritus, and cutaneous T-cell lymphoma (Yosipovitch and Bernhard 2013), while a role of OSM has been described in AD, psoriasis, keratoacanthoma, squamous cell carcinoma, and Kaposi sarcoma (Ameglio et al. 1997; Bonifati et al. 1998; Miles et al. 1992; Nair et al. 1992; Tran et al. 2000). So far, a direct role of IL-6 family cytokines in itch transmission has only been shown for IL-31 (Dillon et al. 2004; Nobbe et al. 2012).

13.1.3. Receptors for IL-31 and OSM

The activities of cytokines are mediated through ligand-induced dimerization of a tyrosine kinase receptor complex.

13.1.3.1. IL-31RA

IL-31 signals through a heterodimeric receptor composed of IL-31RA (gp-130-like receptor) and the OSMRβ subunit. Several subforms of the IL-31RA exist on chromosome 5q11.2, only 24 kb downstream of gp130 (Zhang et al. 2008). Human IL-31RA mRNA, although undetectable in fresh peripheral blood monocytes, is upregulated substantially in monocytes cultured with interferon-γ (IFN-γ) (Dillon et al. 2004). IFN-γ and lipopolysaccharide together induce the expression of both receptor chains of IL-31R in human monocytes (Dillon et al. 2004). In mice, CD4⁺ T cells from IL-31RA–/– mice proliferate stronger and secrete more Th2 cytokines when stimulated under neutral or Th2 conditions, suggesting the presence of IL-31R on mouse CD4⁺ T cells (Perrigoue et al. 2007).

IL-31RA is expressed by DRG neurons, mature dendritic cells, and probably keratinocytes, albeit in the latter two at significantly lower levels (Dillon et al. 2004; Neis et al. 2006; Sonkoly et al. 2006). This is of interest because neuronal expression of IL31RA could indeed mean that IL31 act directly on neuronal expressed IL31RA to induce itch in IL31 overexpressing mice and in atopic dermatitis patients (Figure 13.1).

FIGURE 13.1

During T_H2-dominated inflammation (e.g., atopic dermatitis), and probably in certain T_H2-involved tumors (CTCL), as well as probably prurigo, IL-31 is released from activated skin-homing T_H2 cells. IL-31 binds to the IL-31RA receptor (IL31RA/OSMRβ (more...)

Very recently, the expression of IL-31RA on DRG neurons has been demonstrated on the RNA (Bando et al. 2006; Sonkoly et al. 2006) and protein level (Bando et al. 2006). On the basis of their morphological findings in murine DRG, some authors hypothesize that IL-31 and OSM may have redundant functions in the development of DRGs, while the expression pattern of their functional receptor complexes is different in the developmental period (Bando et al. 2006). A functional role for a neuronally expressed IL-31RA has not been determined until recently.

13.1.3.2. Functional Role of Neuronally Expressed IL-31RA in Itch

Own preliminary data, however, indicate the expression of a functional IL-31RA on DRG neurons (Cevikbas and Steinhoff 2012). First, we used immunohistochemistry, FACS, and qRTPCR to determine IL-31 expression levels in murine atopic-like dermatitis and in human atopic dermatitis (Cevikbas and Steinhoff 2012). We found that among all immune and resident skin cells examined, IL-31 was produced only by T_H2 and mature dendritic cells and was increased in atopic dermatitis. Likewise, the concentration of IL-31 protein was significantly increased in the SAB-induced as well as ovalbumin-induced atopic dermatitis mouse models (Cevikbas et al. 2013). Moreover, using immunohistochemistry, immunofluorecence, qRTPCR, in vivo pharmacology, western blotting, single cell calcium, and electrophysiology, we examined the distribution, functionality, and cellular basis of IL-31RA. In addition to previous studies we found that not only cutaneous (Dillon et al. 2004) but also intrathecal injections of IL-31 evoked intense itch. Interestingly, not only murine but also human DRG neurons express IL-31RA, largely in those that also express TRPV1, indicating a role of IL-31RA in the peptidergic subpopulation of primary afferent nerve fibers. In vivo, we found that IL-31-induced pruritus was significantly reduced in TRPV1- and TRPA1-deficient mice, suggesting for the first time that IL-31RA-mediated itch is linked to TRP channels, namely, TRPV1 and TRPA1 (Cevikbas et al. 2013). Next, we used cultured primary sensory neurons to define the intracellular signaling cascades implicated in IL-31-induced activation of primary afferents and itch. Of note, IL-31 triggered Ca²⁺ release and ERK1/2 phosphorylation, the first linked also to TRPV1 activation, suggesting that IL-31RA-mediated calcium mobilization is associated with intracellular signaling that activates TRPV1 in an intracellular fashion (Cevikbas et al. 2013). In addition, we found that IL-31RA-mediated itch induction is also associated with ERK1/2 phosphorylation because ERK1/2 was significantly activated 5 min after IL-31 application (Cevikbas et al. 2013). Of note, IL-31-induced ERK1/2 activation and scratching behavior was blocked in vivo using a specific inhibitor, suggesting that ERK1/2 is involved in IL-31-induced itch transmission in vitro and in vivo. In conclusion, novel evidence strongly establishes IL-31RA as the first functional neuronally expressed cytokine receptor expressed by a small subpopulation of IL-31RA⁺/TRPV1⁺/TRPA1⁺ nerves. Thus, IL-31RA can be seen as the long-discussed neuroimmune link between subtype-2 T helper (T_H2) cells and sensory nerves for the generation of T-cell-mediated itch. These findings have several important clinical implications because it will improve our understanding of itch in atopic dermatitis and other T_H2-mediated diseases and provides a basis for future targeted drug therapy of itch.

Intriguingly, IL-31 was recently found to be increased in the malignant T-cell population of cutaneous T-cell lymphoma patients (Singer et al. 2013). Previous reports have been suggesting that IL-31 is also increased in CTCL (Miyagaki et al. 2013; Ohmatsu et al. 2012). However, the correlation to the incidence of itch in CTCL patients was not evaluated. In the recently published study, the authors have screened for levels of IL-31 mRNA in different cell types of patient samples. Retrospectively, the high IL-31mRNA levels in the patients reflected nicely the experienced pruritus at time of the sample collection. With cell sorting, the predominant cells with high level of IL-31 protein were defined as CD3⁺CD4⁺CD26^– T lymphocytes that are categorized as malignant cells in CTCL.

Besides the accumulative evidence of IL-31 levels being increased in various pruritic diseases, recent studies also uncovered that genetics might be a potentially relevant aspect in IL-31-related diseases (Hong et al. 2012; Lan et al. 2011). A G-allele variant of IL-31 was linked with higher risks of atopic dermatitis development, suggesting that besides receptor-related missense mutations also the IL-31 gene, variants have impact on the onset of atopic eczema. Indeed, conclusively, a possible treatment against various pruritic diseases might be addressed by neutralizing IL-31 in the patients’ body system.

13.1.3.3. OSMRβ

As all members of the IL-6 family, OSM shares the common signaling receptor subunit gp130 (Kishimoto 1994; Silver and Hunter 2010). Murine OSM stimulates a selective heterodimer composed of the β-subunit of the oncostatin M receptor (OSMRβ) and gp130 (Tanaka et al. 1999). In humans, OSM can also activate the OSMRβ/gp130 heterodimer, but additionally, signaling through the leukemia inhibitory factor receptor (LIFR)/gp130 heterodimer may be triggered as well (Ichihara et al. 1997).

While IL-31RA belongs to the IL-6 receptor family, OSMR is a member of the type-1 cytokine receptor family (Homey et al. 2006). IL-31 and OSM are similar regarding their binding capacity to IL-31RA and gp130, respectively. The latter receptor subunits only convert to high-affinity receptors after forming heterodimer complexes with OSMRβ (Diveu et al. 2004; Gearing et al. 1991, 1992; Mosley et al. 1996). OSM and IL-31 do not cross-activate the other receptor but may have additive or synergistic effects by using interfering signal transduction pathways. This remains to be elucidated.

OSMR mRNA is ubiquitously expressed, with the highest levels in trachea, thymus, and skin (Tamura et al. 2003; Boniface et al. 2007; Morikawa 2005). OSMR mRNA expression can be induced in monocytes treated with lipopolysaccharide. OSMRβ is detectable on keratinocytes and on a subset of nociceptive neurons in dorsal root ganglia (DRG) or trigeminal neurons projecting to the skin. Furthermore, OSMRβ-expressing neurons colocalize with both TRPV1 and P2X3, respectively (Tamura et al. 2003). OSM-deficient mice demonstrate reduced responses to noxious stimuli (Morikawa 2005; Morikawa et al. 2004) and are thus involved in nociception. A recent study showed a direct involvement of OSM in induced heat sensitivity. Thereby OSMR-induced activation of gp130 leads to sensitization TRPV1 in sensory neurons (Langeslag et al. 2011). In OSMRβ-expressing DRG both STAT-3 and cyclic AMP-responsive element binding protein (CREbP) are upregulated (Tamura et al. 2005). Our knowledge about the function of OSMRβ at the neuronal level, however, is very poor as of yet. So far, only a role of OSMRβ has been demonstrated for brain development, especially homeostasis of neural precursor cells, and in nerve degeneration and repair process in response to peripheral nerve injury (Beatus et al. 2011; Ito et al. 2000).

13.1.4. Role of IL-31, OSM and Their Receptors in the Skin

The distribution of IL-31 to OSM and of IL-31 RA to OSMRβ in the skin is almost identical in mice (Bando et al. 2006; Morikawa et al. 2004; Tamura et al. 2003). However, the precise distribution of IL-31RA and OSMRβ in the various subtypes of sensory nerves, their codistribution with other important neuronal mediators or receptors, and their functional role in health and disease is far from being understood. Our own preliminary data strongly favor an important role of IL-31 for the regulation of sensory neurons via IL-31RA activation and signaling (Cevikbas et al. 2011, 2013). The precise role for OSM in murine and human itch has to be explored (Bando et al. 2006; Bilsborough et al. 2006; Weiss et al. 2006).

In the skin, IL-31 exerts functions on cultured keratinocytes, activated macrophages, and dendritic cells (Bilsborough et al. 2006; Dillon et al. 2004; Neis et al. 2006; Novak et al. 2003; Sonkoly et al. 2006). Notably, IL-31RA and OSMRβ have also been described to be expressed by DRG neurons, suggesting a link between T cells and nerves in skin diseases (Bando et al. 2006; Morikawa et al. 2004; Sonkoly et al. 2006). In addition, we found IL-31RA mRNA and protein expression also on human DRG neurons (Cevikbas et al. 2013).

13.1.5. Role of IL-31 and OSM in Itch

13.1.5.1. IL-31

In atopic dermatitis, IL-31 is markedly released by T_H2 cells (Bilsborough et al. 2006; Novak et al. 2003) and is upregulated also in prurigo nodularis, a severely itchy dermatosis (Cevikbas et al. 2013). In AD, T_H2 cells infiltrate the inflamed skin and other organs (Brunn et al. 2008; Zhang et al. 2009) where they can be found closely associated with sensory nerve fibers (Cetin et al. 2009; Huang et al. 2003; Pavlovic et al. 2008; Tanaka et al. 2007). Mice overexpressing IL-31 develop a pruritic atopic-like dermatitis (Dillon et al. 2004). Injection of IL-31 into NC/Nga mice results in sustained pruritus, a characteristic of C-fiber activation (Grimstad et al. 2009). IL-31 gene-deficient mice show less pruritus as compared to wild-type controls (Dillon et al. 2004). Genetic studies on polymorphisms in the human IL-31 gene with respect to the genetic susceptibility to eczema suggest that a haplotype of the IL-31 gene is associated with the intrinsic form of pruritic atopic eczema confirming studies in IL-31 overexpressing and IL-31 RA knockout mice (Schulz et al. 2007; Cevikbas et al. 2011, 2013).

13.1.5.2. OSM

OSM released from T cells is likely to activate keratinocytes through OSMRβ in skin inflammation such as psoriasis and atopic dermatitis (Bando et al. 2006; Boniface et al. 2007; Morikawa 2005). Of importance, in addition to the enhanced expression of OSM and OSMRβ in keratinocytes of atopic dermatitis lesions, OSMRβ mutations have been reported in a familial pruritic skin disease (Arita et al. 2008). Here, a missense mutation in the OSMRβ gene has been shown to be associated with localized cutaneous amyloidosis (FPLCA), a disease with severe chronic pruritus. These data suggest the involvement of the OSM/OSMRβ pathway in pruritus and indicate a role of OSMRβ also in human itch. Thus, it will be important to further characterize the impact of functional IL-31RA and OSMR cytokine receptors on peripheral or central nerves in pruritic skin diseases. IL-31 and OSM may directly or indirectly interact with neurons to modulate itch. Whether both IL-6 family cytokines act synergistically or under different conditions in human disease is currently unknown.

13.1.5.3. Mechanisms of IL-31-Induced Itch

There is substantial evidence that IL-31 and OSM regulate nerves and KC in atopic dermatitis (Arita et al. 2008; Bilsborough et al. 2006; Boniface et al. 2007; Dillon et al. 2004; Homey et al. 2006; Neis et al. 2006; Sonkoly et al. 2006). IL-31-overexpressing mice develop spontaneously an atopic-like dermatitis with severe pruritus (Dillon et al. 2004). In a mouse model of AD (Jin et al. 2009), IL-31RA expression was enhanced (Takaoka et al. 2005), and a monoclonal antibody against IL-31 was capable of ameliorating the scratching behavior, indicating a role of IL-31 in pruritus (Grimstad et al. 2009). However, the important question to which extent IL-31RA and OSMR activation on neurons and KC contribute to these effects in skin inflammation including AD and itch is yet to be explored. IL-31 is significantly upregulated in “pruritic” AD skin as compared to “low- or nonpruritic” psoriatic skin (Sonkoly et al. 2006). Highest IL-31 levels can be detected in prurigo nodularis, representing one of the most pruritic diseases. In vivo, exposure to staphylococcal superantigen rapidly induces IL-31 expression in atopic dermatitis patients (Sonkoly et al. 2006). In vitro, IL-31 is strongly induced by staphylococcal superantigen stimulation. Our own data show that IL-31 induces scratching behavior in mice, confirming previous reports about an important role of IL-31 in the pathophysiology of pruritus (Bilsborough et al. 2006; Dillon et al. 2004; Grimstad et al. 2009; Ishii et al. 2009; Sonkoly et al. 2006; Cevikbas et al. 2011, 2013).

Our studies revealed a novel mechanism of immune-neuron interaction, suggesting a direct interaction between a cytokine receptor on neuronal cells and neuronal receptors. Together, IL-31 and OSM represent direct links between T cells and sensory nerves in the skin. Accordingly, the role of OSM in AD and pruritus is also poorly understood. So far, it is only known that T cells release OSM to activate cytokine release from KC through OSMRβ (Boniface et al. 2007). In summary, the underlying cellular mechanism and the significance of IL-31- and OSM-induced activation of neurons in human disease, however, are still very poorly understood. Moreover, the impact of IL-31RA and OSMR activation on keratinocyte regulation, pruritus and pain have not been investigated as of yet. However, the fact that IL-31 activates a functional IL-31RA on DRG neurons and induces a chronic pruritic skin disease, namely, atopic-like dermatitis, and that antibodies that block IL-31 are beneficial for the treatment of those skin lesions, and that human DRG express IL-31RA strongly indicate a potential therapeutic role of blocking the IL-31/IL-31RA pathway in human T_H2-mediated skin diseases, such as atopic dermatitis or cutaneous T-cell lymphoma.

13.1.5.4. Potential Role of IL-31, OSM, and Their Receptors in Neurogenic Inflammation

During skin inflammation, sensory nerve endings release neuropeptides that regulate vasodilatation (erythema), plasma extravasation (edema), recruitment of inflammatory cells, keratinocyte function (Hanifin 2009; Jin et al. 2009), pruritus (Ikoma et al. 2006; Paus et al. 2006; Steinhoff et al. 2006), or pain sensations (Cavanaugh et al. 2009; Wang et al. 2009). They also modulate immune cells like Langerhans cells, T cells, macrophages, or mast cells (Hanifin 2009). Neuromediators also regulate skin cells such as KC or endothelial cells during inflammation and AD (Haegerstrand et al. 1989; Hosoi et al. 1993; Scholzen et al. 2004). Whether IL-31 and/or OSM regulate neurogenic inflammation in murine or human skin diseases is currently unknown. However, our own data show that IL-31 induces release of calcitonin gene-related peptide (CGRP) from DRG neurons and interacts with TRPV1, a receptor crucially involved in neurogenic inflammation (Caterina et al. 1997), strongly indicating a role of IL-31 in neurogenic inflammation via neuropeptide release and TRPV1 activation. The precise mechanism of IL-31-mediated neurogenic inflammation and the involvement of OSM in this process still need to be explored.

13.1.5.5. Potential Role of IL-31 and OSM in Pain

It has been demonstrated that receptors for kinins, prostanoids, chemokines, and cytokines are involved in the regulation of pain (Ikoma et al. 2006; Zhang and Oppenheim 2005). Recently, an in vivo pain model clearly demonstrated the involvement of IL-6 in the development of heat hyperalgesia by inducing the release of CGRP from rat skin (Opree and Kress 2000). IL-6 shows a sustained increased expression in a model of thermal pain associated with mechanical hyperalgesia suggesting that IL-6 is an important mediator of burn-injury pain (Summer et al. 2008). The blocking of the receptor subunit gp130 by RNA silencing attenuated both burn and intradermal IL-6-induced hyperalgesia (Summer et al. 2008). Our own preliminary data suggest also the involvement of IL-31 in pain transmission (see preliminary results). OSMRβ is expressed in small-sized DRG neurons that are nonpeptidergic but positive for TRPV1 and P2X3, receptors for capsaicin, and ATP, respectively (Tamura et al. 2003). While TRPV1 is activated by protons, heat, and capsaicin, P2X3 is activated by ATP during inflammation or pain. This suggests that OSM produced in the inflamed tissue or during pain may interact with TRPV1 and/or P2X3 in nociceptive neurons, thereby contributing to neurogenic inflammation, sustained pain, or hyperalgesia during inflammation. Whether the IL-6 cytokine family exerts additive or synergistic effects to regulate acute or chronic pain transmission at the peripheral or central level is currently unknown.

13.1.5.6. IL-31/OSM-Related Signal Transduction Pathways in Sensory Neurons

Cytokine receptors of the IL-6 family activate intracellular calcium, STAT signaling, MAP kinases, and others. IL-31 and OSM do not cross-react the receptor of each other (Zhang et al. 2008). However, in order to understand the significance of the codistribution of IL-31RA and OSMRβ in KC, DRGs, and spinal cord neurons, it will be important to fully explore the shared versus nonshared intracellular signaling pathways induced by IL-31, OSM, or both simultaneously. IL-31 induces the MAPK, PI3K pathway (Diveu et al. 2004) and also stimulates the JAK/STAT pathway, predominantly STAT3 and STAT5 (Dillon et al. 2004; Diveu 2003; Dreuw et al. 2004; Ghilardi et al. 2002; Liu et al. 2001). Of note, the Ca2+, MAPK as well as STAT pathways are involved in important neuronal signaling events in DRG and/or spinal cord neurons (Cevikbas et al. 2011, 2013). Although IL-31 and OSM exert important effects on sensory neurons, little is known about IL-31 and OSM-mediated intracellular signaling in the nervous system, their common effects, as well as their specific effects in itch transmission.

13.1.6. Keratinocytes as a “Forefront” of Neuronal Signaling

Keratinocytes release various mediators, e.g., neurotrophins (NGF, NT-4), neuropeptides (SP, ET-1), ATP, proteases, or prostanoids, which subsequently modulate neuronal function like pain or pruritus (reviewed in Ikoma et al. 2006; Paus et al. 2006; Steinhoff et al. 2006). In atopic dermatitis patients, keratinocytes produce and secreted increased levels of the chemokines CCL17, CCL27, and the cytokine thymic stromal lymphopoietin, which are known to be involved in initiating and maintaining inflammatory reactions in the skin by, e.g., inducing maturation of T-cell populations (Lee and Yu 2011). Keratinocytes also express IL-31RA and OSMRβ (Heise et al. 2009). Whether IL-31/OSM modulate neurogenic inflammation, pruritus, and pain via direct activation of IL-31RA (OSMR) receptors on DRG and spinal cord neurons and/or indirectly, via keratinocytes, is currently poorly understood. However, a recent study showed that keratinocyte activation by a TLR2 ligand or IFNγ-induced upregulation of both IL31RA and OSMR (Heise et al. 2009; Kasraie et al. 2011). Activation of IL31RA interferes with keratinocyte differentiation by inducing cell cycle arrest as shown in an organotypic skin model (Cornelissen et al. 2012). Further, the authors showed that IL31RA induced cell cycle arrest of keratinocytes, in turn, inducing striking defects in differentiation associated with reduced epidermal thickness, disturbed constitution, and altered alignment of the basal layer and poor development of the stratum granulosum in the skin model (Cornelissen et al. 2012) This is of interest as in both atopic dermatitis patients and in mice models of atopic-like dermatitis, the epidermis is characterized by hyperkeratosis, leading to a thicker epidermis. However, further studies will be necessary to understand the role of IL31RA activation in keratinocytes for pruritic skin diseases. Moreover, upon stimulation, keratinocytes release cytokine of the IL-1 or IL-6 family that may be key mediators for keratinocyte-sensory nerve interactions controlling neurogenic inflammation or itch. Therefore, in the future, it will be of additional importance to analyze the impact of IL-31 and OSM activation on keratinocytes with respect to their communication with sensory nerves during disease state.

13.2. CONCLUSIONS AND FUTURE DIRECTIONS

Recent results strongly suggest that cytokines of the interleukin-6 family, in particular, IL-31 and OSM, as key players in neuroimmune communication including pain, itch, and probably inflammation. Via IL-31, T_H2 cells “talk” to sensory nerves to induce inflammation and pruritus in atopic dermatitis. Thus, IL-31 and its receptor may be effective targets to treat atopic dermatitis and probably other T_H2-mediated pruritic skin diseases. OSM has been shown to be involved in pain conditions, and a missense mutation of the OSMRβ receptor is involved in severe familial itch of FPLCA patients. Understanding the molecular and cellular basis of IL-31RA and OSMRb-mediated activation of sensory nerves, their signaling and regulation will lead to a novel understanding of cytokine-nerve cross talks in many diseases and to the development of new, innovative drugs for humans suffering from atopic dermatitis and recalcitrant chronic itch, and probably for certain chronic pain conditions. With regard to future directions, our understanding of IL-31 and OSM is underscoring the importance of both cytokines in different diseases (Baumann et al. 2012; Hartmann et al. 2012). IL-31 has been proven to be one very important and reliable biomarker for pruritic skin diseases. Studies measuring the serum levels of IL-31 in humans are indeed increasing the idea that targeting IL-31 via neutralization might be a very promising therapeutic improvement in the treatment of itch.

Novel insights into the molecular mechanisms of IL-31-mediated inflammation and itch of an exclusively immune-cell-derived cytokine acting directly on neurons are of critical importance for our understanding of the cross talk between the immune and nervous systems in acute or chronic inflammation, itch, and pain. Various other cytokines (released from immune cells or nonimmune skin cells) might play a similar role in skin diseases and itch.

ACKNOWLEDGMENTS

This work was supported by research grants from the NIH/NIAMS (R01 5R01AR059402-02), DFG (STE 1014/2-1), ZymoGenetics/BMS (to MS), and the DFG (to F.C., C.K.).

REFERENCES

Ameglio F, Bonifati C, Fazio M. et al. Interleukin-11 production is increased in organ cultures of lesional skin of patients with active plaque-type psoriasis as compared with nonlesional and normal skin. Similarity to interleukin-1 beta, interleukin-6 and interleukin-8. Arch Dermatol Res. 1997;289:399–403. [PubMed: 9248618]
Arita K, South A.P, Hans-Filho G. et al. Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis. Am J Hum Genet. 2008;82:73–80. [PMC free article: PMC2253984] [PubMed: 18179886]
Bamber B, Reife R.A, Haugen H.S. et al. Oncostatin M stimulates excessive extracellular matrix accumulation in a transgenic mouse model of connective tissue disease. J Mol Med. 1998;76:61–69. [PubMed: 9462869]
Bando T, Morikawa Y, Komori T. et al. Complete overlap of interleukin-31 receptor A and oncostatin M receptor beta in the adult dorsal root ganglia with distinct developmental expression patterns. Neuroscience. 2006;142:1263–1271. [PubMed: 16926070]
Baumann R, Rabaszowski M, Stenin I. et al. The release of IL-31 and IL-13 after nasal allergen challenge and their relation to nasal symptoms. Clin Transl Allergy. 2012;2:13. [PMC free article: PMC3509028] [PubMed: 22853438]
Beatus P, Jhaveri D.J, Walker T.L. et al. Oncostatin M regulates neural precursor activity in the adult brain. Dev Neurobiol. 2011;71:619–633. [PubMed: 21671408]
Betz U.A, Bloch W, van den Broek M. et al. Postnatally induced inactivation of gp130 in mice results in neurological, cardiac, hematopoietic, immunological, hepatic, and pulmonary defects. J Exp Med. 1998;188:1955–1965. [PMC free article: PMC2212415] [PubMed: 9815272]
Bilsborough J, Leung D.Y, Maurer M. et al. IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis. J Allergy Clin Immunol. 2006;117:418–425. [PubMed: 16461143]
Boniface K, Diveu C, Morel F. et al. Oncostatin M secreted by skin infiltrating T lymphocytes is a potent keratinocyte activator involved in skin inflammation. J Immunol. 2007;178:4615–4622. [PubMed: 17372020]
Bonifati C, Mussi A, D’Auria L. et al. Spontaneous release of leukemia inhibitory factor and oncostatin-M is increased in supernatants of short-term organ cultures from lesional psoriatic skin. Arch Dermatol Res. 1998;290:9–13. [PubMed: 9522995]
Bonness S, Bieber T. Molecular basis of atopic dermatitis. Curr Opin Allergy Clin Immunol. 2007;7:382–386. [PubMed: 17873576]
Brunn A, Utermohlen O, Carstov M. et al. CD4 T cells mediate axonal damage and spinal cord motor neuron apoptosis in murine p0106-125-induced experimental autoimmune neuritis. Am J Pathol. 2008;173:93–105. [PMC free article: PMC2438288] [PubMed: 18535178]
Caterina M.J, Schumacher M.A, Tominaga M. et al. The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature. 1997;389:816–824. [PubMed: 9349813]
Cavanaugh D.J, Lee H, Lo L. et al. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc Natl Acad Sci USA. 2009;106((22)):9075–9080. [PMC free article: PMC2683885] [PubMed: 19451647]
Cetin E.D, Savk E, Uslu M. et al. Investigation of the inflammatory mechanisms in alopecia areata. Am J Dermatopathol. 2009;31:53–60. [PubMed: 19155726]
Cevikbas F, Steinhoff M. IL-33: A novel danger signal system in atopic dermatitis. J Invest Dermatol. 2012;132:1326–1329. [PMC free article: PMC3694595] [PubMed: 22499037]
Cevikbas F, Steinhoff M, Ikoma A. Role of spinal neurotransmitter receptors in itch: New insights into therapies and drug development. CNS Neurosci Ther. 2011;17:742–749. [PMC free article: PMC6493876] [PubMed: 20950328]
Cevikbas F, Wang X, Akiyama T. et al. A sensory neuron-expressed interleukin-31 receptor mediates T helper cell-dependent pruritus: Involvement of TRPV1 and TRPA1. Submitted to JACI. 2013 [PMC free article: PMC3960328] [PubMed: 24373353]
Chung M.K, Lee H, Caterina M.J. Warm temperatures activate TRPV4 in mouse 308 keratinocytes. J Biol Chem. 2003;278:32037–32046. [PubMed: 12783886]
Chung M.K, Lee H, Mizuno A. et al. TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. J Biol Chem. 2004;279:21569–21575. [PubMed: 15004014]
Cornelissen C, Marquardt Y, Czaja K. et al. IL-31 regulates differentiation and filaggrin expression in human organotypic skin models. J Allergy Clin Immunol. 2012;129:426–433. 33 1-8. [PubMed: 22177328]
Dallos A, Kiss M, Polyanka H. et al. Effects of the neuropeptides substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide and galanin on the production of nerve growth factor and inflammatory cytokines in cultured human keratinocytes. Neuropeptides. 2006;40:251–263. [PubMed: 16904178]
Davis S, Aldrich T.H, Valenzuela D.M. et al. The receptor for ciliary neurotrophic factor. Science. 1991;253:59–63. [PubMed: 1648265]
Derouet D, Rousseau F, Alfonsi F. et al. Neuropoietin, a new IL-6-related cytokine signaling through the ciliary neurotrophic factor receptor. Proc Natl Acad Sci USA. 2004;101:4827–4832. [PMC free article: PMC387333] [PubMed: 15051883]
Dillon S.R, Sprecher C, Hammond A. et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol. 2004;5:752–760. [PubMed: 15184896]
Diveu C, Lak-Hal A.H, Froger J. et al. Predominant expression of the long isoform of GP130-like (GPL) receptor is required for interleukin-31 signaling. Eur Cytokine Netw. 2004;15:291–302. [PubMed: 15627637]
Diveu C, Lelievre E, Perret D. et al. GPL, a novel cytokine receptor related to GP130 and leukemia inhibitory factor receptor. J Biol Chem. 2003;278:49850–49859. [PubMed: 14504285]
Dreuw A, Radtke S, Pflanz S. et al. Characterization of the signaling capacities of the novel gp130-like cytokine receptor. J Biol Chem. 2004;279:36112–36120. [PubMed: 15194700]
Drogemuller K, Helmuth U, Brunn A. et al. Astrocyte gp130 expression is critical for the control of Toxoplasma encephalitis. J Immunol. 2008;181:2683–2693. [PubMed: 18684959]
Duncan M.R, Hasan A, Berman B. Oncostatin M stimulates collagen and glycosaminoglycan production by cultured normal dermal fibroblasts: Insensitivity of sclerodermal and keloidal fibroblasts. J Invest Dermatol. 1995;104:128–133. [PubMed: 7798630]
E Y, Golden S.C, Shalita A.R. et al. Neuropeptide (calcitonin gene-related peptide) induction of nitric oxide in human keratinocytes in vitro. J Invest Dermatol. 2006;126:1994–2001. [PubMed: 16710309]
Ettinger M.P, Littlejohn T.W, Schwartz S.L. et al. Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: A randomized, dose-ranging study. JAMA. 2003;289:1826–1832. [PubMed: 12684362]
Feld M, Shpacovitch V.M, Fastrich M. et al. Interferon-gamma induces upregulation and activation of the interleukin-31 receptor in human dermal microvascular endothelial cells. Exp Dermatol. 2010;19:921–923. [PubMed: 20849534]
Freda M.C, Andersen H.F, Damus K. et al. Lifestyle modification as an intervention for inner city women at high risk for preterm birth. J Adv Nurs. 1990;15:364–372. [PubMed: 2332560]
Gearing D.P, Comeau M.R, Friend D.J. et al. The IL-6 signal transducer, gp130: An oncostatin M receptor and affinity converter for the LIF receptor. Science. 1992;255:1434–1437. [PubMed: 1542794]
Gearing D.P, Thut C.J, VandeBos T. et al. Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gp130. EMBO J. 1991;10:2839–2848. [PMC free article: PMC452994] [PubMed: 1915266]
Ghilardi N, Li J, Hongo J.A. et al. A novel type I cytokine receptor is expressed on monocytes, signals proliferation, and activates STAT-3 and STAT-5. J Biol Chem. 2002;277:16831–16836. [PubMed: 11877449]
Grewe M, Vogelsang K, Ruzicka T. et al. Neurotrophin-4 production by human epidermal keratinocytes: Increased expression in atopic dermatitis. J Invest Dermatol. 2000;114:1108–1112. [PubMed: 10844552]
Grimstad O, Sawanobori Y, Vestergaard C. et al. Anti-interleukin-31-antibodies ameliorate scratching behaviour in NC/Nga mice: A model of atopic dermatitis. Exp Dermatol. 2009;18:35–43. [PubMed: 19054054]
Grothe C, Heese K, Meisinger C. et al. Expression of interleukin-6 and its receptor in the sciatic nerve and cultured Schwann cells: Relation to 18-kD fibroblast growth factor-2. Brain Res. 2000;885:172–181. [PubMed: 11102571]
Guillet C, Auguste P, Mayo W. et al. Ciliary neurotrophic factor is a regulator of muscular strength in aging. J Neurosci. 1999;19:1257–1262. [PMC free article: PMC6786012] [PubMed: 9952403]
Haegerstrand A, Jonzon B, Dalsgaard C.J. et al. Vasoactive intestinal polypeptide stimulates cell proliferation and adenylate cyclase activity of cultured human keratinocytes. Proc Natl Acad Sci USA. 1989;86:5993–5996. [PMC free article: PMC297758] [PubMed: 2474824]
Hanifin J.M. Evolving concepts of pathogenesis in atopic dermatitis and other eczemas. J Invest Dermatol. 2009;129:320–322. [PubMed: 18719604]
Hartmann K, Wagner N, Rabenhorst A. et al. Serum IL-31 levels are increased in a subset of patients with mastocytosis and correlate with disease severity in adult patients. J Allergy Clin Immunol. 2012;132((1)):232–235. [PubMed: 23260756]
Heise R, Neis M.M, Marquardt Y. et al. IL-31 receptor alpha expression in epidermal keratinocytes is modulated by cell differentiation and interferon gamma. J Invest Dermatol. 2009;129:240–243. [PubMed: 18580959]
Helgren M.E, Squinto S.P, Davis H.L. et al. Trophic effect of ciliary neurotrophic factor on denervated skeletal muscle. Cell. 1994;76:493–504. [PubMed: 8313470]
Henderson J.T, Seniuk N.A, Richardson P.M. et al. Systemic administration of ciliary neurotrophic factor induces cachexia in rodents. J Clin Invest. 1994;93:2632–2638. [PMC free article: PMC294503] [PubMed: 8201002]
Hintzen C, Quaiser S, Pap T. et al. Induction of CCL13 expression in synovial fibroblasts highlights a significant role of oncostatin M in rheumatoid arthritis. Arthritis Rheum. 2009;60:1932–1943. [PubMed: 19565514]
Homey B, Steinhoff M, Ruzicka T. et al. Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol. 2006;118:178–189. [PubMed: 16815153]
Hong C.H, Yu H.S, Ko Y.C. et al. Functional regulation of interleukin-31 production by its genetic polymorphism in patients with extrinsic atopic dermatitis. Acta Derm Venereol. 2012;92:430–432. [PubMed: 21952721]
Hosoi J, Murphy G.F, Egan C.L. et al. Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide. Nature. 1993;363:159–163. [PubMed: 8483499]
Huang C.H, Kuo I.C, Xu H. et al. Mite allergen induces allergic dermatitis with concomitant neurogenic inflammation in mouse. J Invest Dermatol. 2003;121:289–293. [PubMed: 12880420]
Huang S.M, Lee H, Chung M.K. et al. Overexpressed transient receptor potential vanilloid 3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2. J Neurosci. 2008;28:13727–13737. [PMC free article: PMC2676929] [PubMed: 19091963]
Hui W, Bell M, Carroll G. Detection of oncostatin M in synovial fluid from patients with rheumatoid arthritis. Ann Rheum Dis. 1997;56:184–187. [PMC free article: PMC1752333] [PubMed: 9135222]
Ibrahim M.M, Porreca F, Lai J. et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci USA. 2005;102:3093–3098. [PMC free article: PMC549497] [PubMed: 15705714]
Ichihara M, Hara T, Kim H. et al. Oncostatin M and leukemia inhibitory factor do not use the same functional receptor in mice. Blood. 1997;90:165–173. [PubMed: 9207450]
Ihn H, Tamaki K. Oncostatin M stimulates the growth of dermal fibroblasts via a mitogen-activated protein kinase-dependent pathway. J Immunol. 2000;165:2149–2155. [PubMed: 10925301]
Ikoma A, Steinhoff M, Stander S. et al. The neurobiology of itch. Nat Rev Neurosci. 2006;7:535–547. [PubMed: 16791143]
Ishii T, Wang J, Zhang W. et al. Pivotal role of mast cells in pruritogenesis in patients with myeloproliferative disorders. Blood. 2009;113((23)):5942–5950. [PubMed: 19196660]
Ishiuji Y, Coghill R.C, Patel T.S. et al. Repetitive scratching and noxious heat do not inhibit histamine-induced itch in atopic dermatitis. Br J Dermatol. 2008;158:78–83. [PubMed: 17986304]
Ito Y, Yamamoto M, Li M. et al. Temporal expression of mRNAs for neuropoietic cytokines, interleukin-11 (IL-11), oncostatin M (OSM), cardiotrophin-1 (CT-1) and their receptors (IL-11Ralpha and OSMRbeta) in peripheral nerve injury. Neurochem Res. 2000;25:1113–1118. [PubMed: 11055749]
Jin H, He R, Oyoshi M. et al. Animal models of atopic dermatitis. J Invest Dermatol. 2009;129:31–40. [PMC free article: PMC2886143] [PubMed: 19078986]
Jones J.L, Anderson J.M, Phuah C.L. et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain. 2010;133:2232–2247. [PubMed: 20659956]
Kakurai M, Fujita N, Murata S. et al. Vasoactive intestinal peptide regulates its receptor expression and functions of human keratinocytes via type I vasoactive intestinal peptide receptors. J Invest Dermatol. 2001;116:743–749. [PubMed: 11348464]
Kamiya A, Kinoshita T, Ito Y. et al. Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer. EMBO J. 1999;18:2127–2136. [PMC free article: PMC1171297] [PubMed: 10205167]
Kasraie S, Niebuhr M, Baumert K. et al. Functional effects of interleukin 31 in human primary keratinocytes. Allergy. 2011;66:845–852. [PubMed: 21261663]
Kishimoto T. 1994. Signal transduction through homo- or heterodimers of gp130 Stem Cells 12(Suppl 1) 37 44discussion 44–45 . [PubMed: 7696968]
Kokoeva M.V, Yin H, Flier J.S. Neurogenesis in the hypothalamus of adult mice: Potential role in energy balance. Science. 2005;310:679–683. [PubMed: 16254185]
Lacreusette A, Nguyen J.M, Pandolfino M.C. et al. Loss of oncostatin M receptor beta in metastatic melanoma cells. Oncogene. 2007;26:881–892. [PubMed: 16909117]
Lan C.C, Tu H.P, Wu C.S. et al. Distinct SPINK5 and IL-31 polymorphisms are associated with atopic eczema and non-atopic hand dermatitis in Taiwanese nursing population. Exp Dermatol. 2011;20:975–979. [PubMed: 22017185]
Langdon C, Kerr C, Hassen M. et al. Murine oncostatin M stimulates mouse synovial fibroblasts in vitro and induces inflammation and destruction in mouse joints in vivo. Am J Pathol. 2000;157:1187–1196. [PMC free article: PMC1850181] [PubMed: 11021823]
Langeslag M, Constantin C.E, Andratsch M. et al. Oncostatin M induces heat hypersensitivity by gp130-dependent sensitization of TRPV1 in sensory neurons. Mol Pain. 2011;7:102. [PMC free article: PMC3275481] [PubMed: 22196363]
Lee C.H, Yu H.S. Biomarkers for itch and disease severity in atopic dermatitis. Curr Probl Dermatol. 2011;41:136–148. [PubMed: 21576954]
LeMaster A.M, Krimm R.F, Davis B.M. et al. Overexpression of brain-derived neurotrophic factor enhances sensory innervation and selectively increases neuron number. J Neurosci. 1999;19:5919–5931. [PMC free article: PMC6783078] [PubMed: 10407031]
Liou J.T, Mao C.C, Ching-Wah Sum D. et al. Peritoneal administration of Met-RANTES attenuates inflammatory and nociceptive responses in a murine neuropathic pain model. J Pain. 2013;14:24–35. [PubMed: 23183003]
Liou J.T, Yuan H.B, Mao C.C. et al. Absence of C-C motif chemokine ligand 5 in mice leads to decreased local macrophage recruitment and behavioral hypersensitivity in a murine neuropathic pain model. Pain. 2012;153:1283–1291. [PubMed: 22494919]
Liu B, Gross M, ten Hoeve J. et al. A transcriptional corepressor of Stat1 with an essential LXXLL signature motif. Proc Natl Acad Sci USA. 2001;98:3203–3207. [PMC free article: PMC30631] [PubMed: 11248056]
Liu T, Jiang C.Y, Fujita T. et al. Enhancement by interleukin-1beta of AMPA and NMDA receptor-mediated currents in adult rat spinal superficial dorsal horn neurons. Mol Pain. 2013;9:16. [PMC free article: PMC3622562] [PubMed: 23537341]
Matthews V.B, Febbraio M.A. CNTF: A target therapeutic for obesity-related metabolic disease? J Mol Med. 2008;86:353–361. [PubMed: 18210031]
McGregor N.E, Poulton I.J, Walker E.C. et al. Ciliary neurotrophic factor inhibits bone formation and plays a sex-specific role in bone growth and remodeling. Calcif Tissue Int. 2010;86:261–270. [PubMed: 20157807]
Miles S.A, Martinez-Maza O, Rezai A. et al. Oncostatin M as a potent mitogen for AIDS-Kaposi’s sarcoma-derived cells. Science. 1992;255:1432–1434. [PubMed: 1542793]
Miyagaki T, Sugaya M, Suga H. et al. Increased CCL18 expression in patients with cutaneous T-cell lymphoma: Association with disease severity and prognosis. J Eur Acad Dermatol Venereol. 2013;27:e60–e67. [PubMed: 22404649]
Miyajima A, Kinoshita T, Tanaka M. et al. Role of oncostatin M in hematopoiesis and liver development. Cytokine Growth Factor Rev. 2000;11:177–183. [PubMed: 10817961]
Morikawa Y. Oncostatin M in the development of the nervous system. Anat Sci Int. 2005;80:53–59. [PubMed: 15794131]
Morikawa Y, Tamura S, Minehata K. et al. Essential function of oncostatin m in nociceptive neurons of dorsal root ganglia. J Neurosci. 2004;24:1941–1947. [PMC free article: PMC6730413] [PubMed: 14985435]
Mosley B, De Imus C, Friend D. et al. Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation. J Biol Chem. 1996;271:32635–32643. [PubMed: 8999038]
Mukouyama Y, Hara T, Xu M. et al. In vitro expansion of murine multipotential hematopoietic progenitors from the embryonic aorta-gonad-mesonephros region. Immunity. 1998;8:105–114. [PubMed: 9462516]
Nair B.C, DeVico A.L, Nakamura S. et al. Identification of a major growth factor for AIDS-Kaposi’s sarcoma cells as oncostatin M. Science. 1992;255:1430–1432. [PubMed: 1542792]
Neis M.M, Peters B, Dreuw A. et al. Enhanced expression levels of IL-31 correlate with IL-4 and IL-13 in atopic and allergic contact dermatitis. J Allergy Clin Immunol. 2006;118:930–937. [PubMed: 17030248]
Nobbe S, Dziunycz P, Muhleisen B. et al. IL-31 expression by inflammatory cells is preferentially elevated in atopic dermatitis. Acta Derm Venereol. 2012;92:24–28. [PubMed: 22041865]
Novak N, Bieber T, Leung D.Y. Immune mechanisms leading to atopic dermatitis. J Allergy Clin Immunol. 2003;112:S128–S139. [PubMed: 14657843]
Ohmatsu H, Sugaya M, Suga H. et al. Serum IL-31 levels are increased in patients with cutaneous T-cell lymphoma. Acta Derm Venereol. 2012;92:282–283. [PubMed: 22456907]
Ohno M, Kohyama J, Namihira M. et al. Neuropoietin induces neuroepithelial cells to differentiate into astrocytes via activation of STAT3. Cytokine. 2006;36:17–22. [PubMed: 17161614]
Ong P.Y, Leung D.Y. Immune dysregulation in atopic dermatitis. Curr Allergy Asthma Rep. 2006;6:384–389. [PubMed: 16899200]
Opree A, Kress M. Involvement of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1 beta, and IL-6 but not IL-8 in the development of heat hyperalgesia: Effects on heat-evoked calcitonin gene-related peptide release from rat skin. J Neurosci. 2000;20:6289–6293. [PMC free article: PMC6772609] [PubMed: 10934280]
Ouyang L, Shen L.Y, Li T. et al. Inhibition effect of Oncostatin M on metastatic human lung cancer cells 95-D in vitro and on murine melanoma cells B16BL6 in vivo. Biomed Res. 2006;27:197–202. [PubMed: 16971773]
Paus R, Schmelz M, Biro T. et al. Frontiers in pruritus research: Scratching the brain for more effective itch therapy. J Clin Invest. 2006;116:1174–1186. [PMC free article: PMC1451220] [PubMed: 16670758]
Pavlovic S, Daniltchenko M, Tobin D.J. et al. Further exploring the brain-skin connection: Stress worsens dermatitis via substance P-dependent neurogenic inflammation in mice. J Invest Dermatol. 2008;128:434–446. [PubMed: 17914449]
Perrigoue J.G, Li J, Zaph C. et al. IL-31-IL-31R interactions negatively regulate type 2 inflammation in the lung. J Exp Med. 2007;204:481–487. [PMC free article: PMC2137900] [PubMed: 17353366]
Raychaudhuri S.P, Jiang W.Y, Raychaudhuri S.K. Revisiting the Koebner phenomenon: Role of NGF and its receptor system in the pathogenesis of psoriasis. Am J Pathol. 2008;172:961–971. [PMC free article: PMC2276420] [PubMed: 18349121]
Repovic P, Benveniste E.N. Prostaglandin E2 is a novel inducer of oncostatin-M expression in macrophages and microglia. J Neurosci. 2002;22:5334–5343. [PMC free article: PMC6758185] [PubMed: 12097485]
Roosterman D, Goerge T, Schneider S.W. et al. Neuronal control of skin function: The skin as a neuroimmunoendocrine organ. Physiol Rev. 2006;86:1309–1379. [PubMed: 17015491]
Saika F, Kiguchi N, Kobayashi Y. et al. CC-chemokine ligand 4/macrophage inflammatory protein-1beta participates in the induction of neuropathic pain after peripheral nerve injury. Eur J Pain. 2012;16:1271–1280. [PubMed: 22528550]
Scholzen T.E, Steinhoff M, Sindrilaru A. et al. Cutaneous allergic contact dermatitis responses are diminished in mice deficient in neurokinin 1 receptors and augmented by neurokinin 2 receptor blockage. FASEB J. 2004;18:1007–1009. [PubMed: 15084523]
Schulz F, Marenholz I, Folster-Holst R. et al. A common haplotype of the IL-31 gene influencing gene expression is associated with nonatopic eczema. J Allergy Clin Immunol. 2007;120:1097–1102. [PubMed: 17900679]
Sehra S, Tuana F.M, Holbreich M. et al. Scratching the surface: Towards understanding the pathogenesis of atopic dermatitis. Crit Rev Immunol. 2008;28:15–43. [PubMed: 18298382]
Sendtner M, Schmalbruch H, Stockli K.A. et al. Ciliary neurotrophic factor prevents degeneration of motor neurons in mouse mutant progressive motor neuronopathy. Nature. 1992;358:502–504. [PubMed: 1641039]
Silver J.S, Hunter C.A. gp130 at the nexus of inflammation, autoimmunity, and cancer. J Leukoc Biol. 2010;88:1145–1156. [PMC free article: PMC2996896] [PubMed: 20610800]
Singer E.M, Shin D.B, Nattkemper L.A. et al. 2013. Interleukin-31 is produced by the malignant T-cell population in cutaneous T-cell lymphoma and correlates with CTCL pruritus J Invest Dermatol doi:10.1038/jid.2013.227 [Epub ahead of print] [PubMed: 23698099]
Sleeman M.W, Anderson K.D, Lambert P.D. et al. The ciliary neurotrophic factor and its receptor, CNTFR alpha. Pharm Acta Helv. 2000;74:265–272. [PubMed: 10812968]
Sleeman M.W, Garcia K, Liu R. et al. Ciliary neurotrophic factor improves diabetic parameters and hepatic steatosis and increases basal metabolic rate in db/db mice. Proc Natl Acad Sci USA. 2003;100:14297–14302. [PMC free article: PMC283586] [PubMed: 14610276]
Sonkoly E, Muller A, Lauerma A.I. et al. IL-31: A new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol. 2006;117:411–417. [PubMed: 16461142]
Steinhoff M, Bienenstock J, Schmelz M. et al. Neurophysiological, neuroimmunological, and neuroendocrine basis of pruritus. J Invest Dermatol. 2006;126:1705–1718. [PubMed: 16845410]
Steinhoff M, Groves R, LeBoit P. Inflammation. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. In Rook’s Textbook of Dermatology. 8th. Blackwell; Malden, MA: 2010. pp. 10.1–10.69.
Steinhoff M, Neisius U, Ikoma A. et al. Proteinase-activated receptor-2 mediates itch: A novel pathway for pruritus in human skin. J Neurosci. 2003;23:6176–6180. [PMC free article: PMC6740542] [PubMed: 12867500]
Steinhoff M, Vergnolle N, Young S.H. et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med. 2000;6:151–158. [PubMed: 10655102]
Stockli K.A, Lillien L.E, Naher-Noe M. et al. Regional distribution, developmental changes, and cellular localization of CNTF-mRNA and protein in the rat brain. J Cell Biol. 1991;115:447–459. [PMC free article: PMC2289163] [PubMed: 1918150]
Summer G.J, Romero-Sandoval E.A, Bogen O. et al. Proinflammatory cytokines mediating burn-injury pain. Pain. 2008;135:98–107. [PubMed: 17590515]
Takaoka A, Arai I, Sugimoto M. et al. Expression of IL-31 gene transcripts in NC/Nga mice with atopic dermatitis. Eur J Pharmacol. 2005;516:180–181. [PubMed: 15925362]
Tamura S, Morikawa Y, Miyajima A. et al. Expression of oncostatin M in hematopoietic organs. Dev Dyn. 2002;225:327–331. [PubMed: 12412016]
Tamura S, Morikawa Y, Miyajima A. et al. Expression of oncostatin M receptor beta in a specific subset of nociceptive sensory neurons. Eur J Neurosci. 2003;17:2287–2298. [PubMed: 12814362]
Tamura S, Morikawa Y, Senba E. Localization of oncostatin M receptor beta in adult and developing CNS. Neuroscience. 2003;119:991–997. [PubMed: 12831858]
Tamura S, Morikawa Y, Senba E. Up-regulated phosphorylation of signal transducer and activator of transcription 3 and cyclic AMP-responsive element binding protein by peripheral inflammation in primary afferent neurons possibly through oncostatin M receptor. Neuroscience. 2005;133:797–806. [PubMed: 15893881]
Tanaka A, Muto S, Jung K. et al. Topical application with a new NF-kappaB inhibitor improves atopic dermatitis in NC/NgaTnd mice. J Invest Dermatol. 2007;127:855–863. [PubMed: 17068475]
Tanaka M, Hara T, Copeland N.G. et al. Reconstitution of the functional mouse oncostatin M (OSM) receptor: Molecular cloning of the mouse OSM receptor beta subunit. Blood. 1999;93:804–815. [PubMed: 9920829]
Tran T.A, Ross J.S, Sheehan C.E. et al. Comparison of oncostatin M expression in keratoacanthoma and squamous cell carcinoma. Mod Pathol. 2000;13:427–432. [PubMed: 10786810]
Vlotides G, Zitzmann K, Stalla G.K. et al. Novel neurotrophin-1/B cell-stimulating factor-3 (NNT-1/BSF-3)/cardiotrophin-like cytokine (CLC)—A novel gp130 cytokine with pleiotropic functions. Cytokine Growth Factor Rev. 2004;15:325–336. [PubMed: 15450249]
Wang X, Ratnam J, Zou B. et al. TrkB signaling is required for both the induction and maintenance of tissue and nerve injury-induced persistent pain. J Neurosci. 2009;29:5508–5515. [PMC free article: PMC2720992] [PubMed: 19403818]
Weiss T.W, Samson A.L, Niego B. et al. Oncostatin M is a neuroprotective cytokine that inhibits excitotoxic injury in vitro and in vivo. FASEB J. 2006;20:2369–2371. [PubMed: 17023520]
Yoshida K, Taga T, Saito M. et al. Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proc Natl Acad Sci USA. 1996;93:407–411. [PMC free article: PMC40247] [PubMed: 8552649]
Yosipovitch G, Bernhard J.D. Clinical practice. Chronic pruritus. N Engl J Med. 2013;368:1625–1634. [PubMed: 23614588]
Yosipovitch G, Greaves M.W, Schmelz M. Itch. Lancet. 2003;361:690–694. [PubMed: 12606187]
Yosipovitch G, Papoiu A.D. What causes itch in atopic dermatitis? Curr Allergy Asthma Rep. 2008;8:306–311. [PubMed: 18606082]
Zhang N, Oppenheim J.J. Crosstalk between chemokines and neuronal receptors bridges immune and nervous systems. J Leukoc Biol. 2005;78:1210–1214. [PubMed: 16204635]
Zhang Q, Putheti P, Zhou Q. et al. Structures and biological functions of IL-31 and IL-31 receptors. Cytokine Growth Factor Rev. 2008;19:347–356. [PMC free article: PMC2659402] [PubMed: 18926762]
Zhang Z.J, Dong Y.L, Lu Y. et al. Chemokine CCL2 and its receptor CCR2 in the medullary dorsal horn are involved in trigeminal neuropathic pain. J Neuroinflammation. 2012;9:136. [PMC free article: PMC3391989] [PubMed: 22721162]
Zhang Z.Y, Zhang Z, Fauser U. et al. Expression of interleukin-16 in sciatic nerves, spinal roots and spinal cords of experimental autoimmune neuritis rats. Brain Pathol. 2009;19:205–213. [PMC free article: PMC8094815] [PubMed: 18462471]

Bookshelf ID: NBK200913PMID: 24830021

Contents