Cytokine Regulation of Cholangiocyte Growth

Yoko Yamagiwa; Tushar Patel

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Cytokine Regulation of Cholangiocyte Growth

Yoko Yamagiwa and Tushar Patel.

Cytokines are mediator molecules which coordinate communication between different cell types and tissues. Recent studies have shown that cholangiocytes can produce as well as respond to cytokines. Several cytokines such as interleukin-6, transforming growth factor beta and tumor necrosis factor alpha are involved in the regulation of biliary epithelial growth. Aberrant signaling in response to growth modulatory cytokines may impair tissue repair processes in diseases affecting the bile ducts, as well as promote the growth of malignant cholangiocytes. Thus, elucidation of the mechanisms by which cytokines regulate cholangiocyte growth, and their specific involvement in pathophysiological settings may ultimately result in improved therapeutic interventions for the cholangiopathies.

Background

Cytokines are hormonal mediators of cellular interactions within and between body tissues. These soluble, low-molecular weight molecules are released by host cells and act, typically in low concentrations, to regulate cell function. While originally described as being produced by cells of immune lineage, cytokines have now been shown to be produced by a variety of epithelial cells. Within the liver, cytokines are produced by hepatocytes, sinusoidal endothelial cells, Kupffer cells and hepatic stellate cells. In addition, recent studies have shown that biliary epithelial cells can also produce as well as respond to cytokines.

Cytokines and Biliary Epithelia

The epithelial lining of the biliary tract can be exposed to inflammatory cytokines from a variety of sources (fig. 1). Extrahepatically produced cytokines can target the biliary epithelia via the arterial circulation. Luminal inflammation during cholangitis or parasitic infection of the bile ducts can expose the biliary epithelia to inflammatory mediators and cytokines. Intrahepatic sources such as inflammatory cells, or other hepatic cells can release cytokines into the microenvironment. Finally cholangiocytes themselves can secrete cytokines, thereby facilitating autocrine and paracrine regulation of various activities in biliary epithelial as well as other hepatic cells.¹^-³ Cholangiocytes can produce a variety of cytokines under normal conditions. These cytokines include inflammatory mediators such as interleukin-6 (IL-6), transforming growth factor beta (TGFβ), tumor necrosis factor-alpha (TNFα), IL-8, and platelet-derived growth factor (PDGF) B chain.¹^,⁴^,⁵

Figure 1

Sources of cytokines. Biliary epithelia can produce and respond to a variety of cytokines. Some of these may be elaborated directly by the biliary epithelial cell, and act in an autocrine or paracrine manner. Locally produced cytokines may be released (more...)

Cholangiocytes can respond to cytokines in a variety of ways. Cholangiocytes can be a target of inflammation-associated cytokines in autoimmune, infectious, neoplastic or developmental cholangiopathies. Inflammatory cytokines may mediate a cellular injury response such as by stimulating an immune response, promoting tissue fibrosis, altering cellular functions such as transport, or by regulation of tissue growth through modulation of apoptosis or proliferation. The biliary tract epithelium may directly suffer cytokine-mediated immunological damage in Primary Biliary Cirrhosis (PBC) and allograft rejection, or indirectly following host cell responses to luminal obstruction or infection. Although the role of inflammatory cytokines as effectors of immune mediated cholangiocyte injury is being increasingly appreciated, little is known about the role of cytokines in other cellular processes such as proliferation. In most situations where chronic inflammation and biliary damage occur, proliferation of bile duct cells organized in ductules and pseudotubules is also seen. Bile duct proliferation can contribute to the development of cirrhosis by disruption of the limiting plate and production of basement proteins, termed as the “bile ductular reaction” by Popper.⁶ Thus understanding the proliferative responses of cholangiocytes to cytokines is germane to a wide range of clinical conditions. Cell growth in multicellular organisms requires continuous cues from the extracellular environment and non-cell autonomous communication is required to maintain homeostasis. As key intercellular signaling mediators, cytokines are likely to be involved in the regulation of cholangiocyte growth in normal or diseased bile ducts as well as in malignant cell growth in bile duct cancers. However, the involvement of individual cytokines in the modulation of epithelial cell proliferation is poorly understood and likely to be complex. Nevertheless, several cytokines such as IL-6, TGFβ and TNFα have been implicated in human biliary epithelial cell growth.¹^,³ An understanding of the role of these and other cytokine mediators of biliary epithelial cell proliferation is essential both in terms of understanding normal growth regulation, as well as during altered growth in biliary tract malignancies.

Cytokine Mediated Growth Regulation in Pathophysiological Processes

Pathophysiological processes in which cholangiocyte growth may be regulated by cyokines include acute or chronic inflammation, following hepatic injury, during tissue regeneration and tumor cell growth.

Hepatic Regeneration

Cellular mitogenic signals mediated by cytokines play an important role in maintaining tissue homeostasis following hepatic injury.⁷ Following partial hepatectomy, the majority of cells in the remnant liver undergo a transition from the quiescent or G0 phase into the G1 phase of the cell cycle. The signals that mediate this transformation are not clearly understood, but a number of cytokines and other signaling events have been implicated in this process. For precise liver regeneration, multiple hepatic cell types must proliferate in a coordinated fashion. This is most likely achieved by cell-to-cell communication or paracrine effects of growth factors or cytokines. Partial hepatectomy releases cytokines such as IL-1, IL-6, and TNFα. Pretreatment of normal mice with lipopolysaccharide (LPS), an activator of cytokine production, augments DNA synthesis. Furthermore, serum IL-6 concentrations increase significantly after partial hepatectomy, and this effect may be inhibited by antibodies to TNFα, a factor known to trigger IL-6 release. These experimental observations provide evidence for the involvement of cytokines in the cellular changes mediating regeneration. The temporal relationship of cholangiocyte proliferation to hepatocyte proliferation following partial hepatectomy suggests a primary role for cytokines released by hepatocytes or nonparenchymal cells. However the signaling molecules involved in the regulation of cholangiocyte proliferation during hepatic regeneration are unknown. Comparative studies of gene expression in isolated cholangiocytes and other nonparenchymal cells from regenerating livers are required to fully understand these processes.

Systemic Inflammation

The systemic response to acute inflammation, infection or tissue injury, referred to as the acute phase response, encompasses a wide range of physiological changes that are initiated immediately after the physical insult has occurred. Among these changes is a marked alteration in the biosynthetic profile of the liver, resulting in a dramatic increase in the synthesis and secretion of several proteins referred to as the acute phase reactants. This increase is largely controlled at the transcriptional level, and mediated by a series of inflammatory cytokines, namely IL-6 and IL-1, as well as glucocorticoids and growth factors. The specific effects of systemic inflammation on cholangiocyte growth and function are unknown, but IL-1 stimulates production of IL-6, a potent biliary epithelial mitogen in vitro, and high levels of inflammatory cytokines may be present in bile.⁸

Biliary Tract Inflammation

Alterations in cytokine mediated tissue homeostasis may occur in response to persistent cytokine stimulation during chronic biliary tract inflammation.⁹ The process of inflammation has many predictable features, reflecting a series of events which is coordinated to a large extent through cytokines.¹⁰ In clinical practice chronic biliary tract inflammation occurs in conditions such as primary sclerosing cholangitis, hepatolithiasis, and chronic parasitic infections. All of these conditions predispose to the development of cholangiocarcinoma. Since cytokines are key mediators of inflammatory processes, a reasonable postulate is that dysregulation of cytokine expression or signaling may contribute to tumorigenesis in the biliary tract.

Tumor Cell Growth

The multi-stage paradigm of carcinogenesis in hepatic and other epithelia predicts a stepwise progression from normality to malignancy. The first step, initiation, may result following genotoxic injury but is often spontaneous. Initiation likely occurs in single cells which replicate and gradually form larger clones. The next step of carcinogenesis is tumor promotion, which accelerates the growth rate of these clones. Progression involves the selection of cells within these clones with higher proliferative potential. Agents promoting tumorigenesis may accelerate cell growth, inhibit cell death or cause phenotypic alterations conferring a survival advantage. Thus dysregulation of cell growth is a critical determinant of neoplastic evolution. Altered signaling in response to growth modulatory cytokines promotes cholangiocarcinoma growth. Indeed, cytokines such as IL-6 and TGFβ have been implicated in the growth regulation of biliary tract malignancies. Thus tumor cell growth may be promoted by increased responsiveness to mito-stimulatory cytokines such as IL-6, or decreased responsiveness to mito-inhibitory cytokines such as TGFβ.

Cytokine Regulation of Biliary Epithelial Proliferation

Establishing a specific role for cytokines in physiological or pathophysiological situations is difficult due to the large number of cytokines that may be present and the excessive redundancy and pleiotropy of cytokine systems. However, individual cytokines may have special, even unique roles in growth regulation. Experimental evidence supports a role for selected cytokines in cholangiocyte proliferation. In this section, we will review the role and involvement of IL-6, a mito-stimulatory cytokine, and TGFβ, a mito-inhibitory cytokine, in the regulation of cholangiocyte growth.

Interleukin-6

IL-6 is a multi-functional cytokine which exerts growth-inducing, growth-inhibitory and differentiation-inducing effects in a cell-type specific manner. We have shown that cholangiocytes constitutively secrete IL-6, and that production is greatly increased in response to inflammatory stimuli such as lipolysaccharide as well as the pro-inflammatory cytokines IL-6 or TNFα.¹¹ IL-6 has been shown to be a potent mitogen for human cholangiocytes.¹^,¹²^,¹³ The ability of this pro-inflammatory cytokine to directly promote cholangiocyte DNA synthesis thus provides a link between liver inflammation and the reparative growth response. Furthermore, the demonstration that cholangiocytes can both produce as well as respond to IL-6 supports the presence of an autocrine growth control loop similar to those that have been described for glomerular mesangial and melanoma cells in humans. ¹² Several investigators including ourselves have also demonstrated that IL-6 is a potent mitogen for malignant cholangiocytes.¹⁴^,¹⁵

IL-6 is a member of a family of broadly acting cytokines whose cognate receptors share the common signal-transducing component gp130.¹⁶ This family includes leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNF), IL-11, cardiotrophin-1 (CT-1) and oncostatin M. IL-6 interacts sequentially with two receptor subunits with distinct functions, the ligand binding subunit IL6R (gp80) and the signal transducing chain gp130, and assembles a hexameric receptor complex formed by two IL6/two IL6R and two gp130 molecules.¹⁶ Double transgenic mice expressing both human IL-6 and a soluble form of IL-6R develop dramatic liver specific abnormalities including a prominent liver nodular hyperplasia further emphasizing the involvement of IL-6 in hepatic pathophysiology. Signal transduction in response to IL-6 occurs primarily via two well-defined pathways: (a) the Ras/Mitogen Activated Protein Kinase (MAPK) pathway and (b) the Jak/Stat pathway.¹⁶ Induction of these pathways results in the enhanced activity of a set of transcription factors that specifically mediate the increased expression of the acute phase reactants: C/EBPβ/NF-IL6 and C/EBPδ are activated via the Ras/MAPK pathway, while the Stat3/APRF is activated by the Jak/Stat pathway.

We and others have shown that IL-6 is produced by normal cholangiocytes.¹^,¹¹ Expression of IL-6 is modulated in diseases such as primary biliary cirrhosis, extrahepatic bile duct obstruction, and chronic hepatitis B or C viral infection. IL-6 can also act as a potent mitogen for cholangiocytes, following stimulation by inflammatory mediators such as IL-1 beta, phorbol myristate acetate, TNFα, or LPS.¹^,¹¹ Additional support for a role of IL-6 in cholangiocyte proliferation is provided by studies in rodent models of cholangiocyte proliferation during bile duct ligation (BDL). In these models, cholangiocyte expression of IL-6R/gp80 was observed at later time points. Interestingly, cholangiocyte proliferation was not observed after BDL or partial hepatectomy in IL-6 deficient mice. These studies indicate that proliferation of BDL cholangiocytes depends on IL-6 production.

Human cholangiocytes express both subunits of IL-6 receptor, and respond to IL-6 by activation of MAPK signaling pathways. Similarly, increased IL-6 secretion has been observed in malignant cholangiocytes. The ability of human malignant cholangiocytes to proliferate in response to IL-6 suggests the presence of autocrine or paracrine growth regulatory mechanisms. The inverse correlation of IL-6 expression with degree of differentiation in cholangiocarcinoma reported by Sugawara et al. may indicate that cholangiocarcinoma may become independent of IL-6 signal as its differentiation advances.¹⁷

We have previously demonstrated activation of the p44/p42 MAPK signaling pathway by IL-6 in H69 cells, human nonmalignant cholangiocytes.¹¹ The p44/p42 MAPK pathway mediates cell proliferation and DNA synthesis in response to IL-6. However, IL-6 activated not only p44/p42 but also the p38 MAPK pathways in KMCH malignant cholangiocytes. Both pathways are involved in IL-6 mediated proliferation in these cells.¹⁵ Furthermore, the p38 MAPK mediates anchorage-independent as well as anchorage-dependent growth, while p44/p42 pathway was involved only in anchorage-dependent growth.¹⁸ Taken together, IL-6 exerts effects through either p44/p42 or p38 pathways in cholangiocarcinoma in a cell-type specific manner (fig. 2), and that activation of the p38 MAPK signaling pathway may promote the malignant phenotype. Aberrant activation of the p38 MAPK signaling pathway in malignant but not in nonmalignant tissues offers the potential for selective manipulation of p38 MAPK in the inhibition of tumor cell growth.

Figure 2

Interleukin-stimulated mitogen-activated protein kinases in cholangiocytes. IL-6 is mitogenic for normal human biliary epithelia, as well as for malignant human biliary epithelial cells. However, the intracellular signals elicited vary. Although the p44/p42 (more...)

Transforming Growth Factor-beta (TGF βββββ)

TGFβ is a multi-functional cytokine involved in cell growth and differentiation.¹⁹ This pleiotropic cytokine has an inhibitory effect on cell proliferation in many epithelial cells, while having a stimulatory effect on mesenchymal cells. TGFβ has been implicated in biliary epithelial proliferation in clinical as well as experimental biliary tract disease.²⁰

Three distinct isoforms of TGFβ have been identified in mammals, and they exert their effects through the same receptor-signaling system. TGFβ is secreted as an inactive complex, constituted with TGF-β dimer, latency-associated proteins (LAP) and latent TGFβ-binding proteins (LTBP). The complex is activated by protease such as plasmin, matrix metalloproteinases (MMP), thrombospondin, and receptors including integrins and mannose 6-phosphate/insulin-like growth factor II (M6P/IGF-II). TGFβ receptor consists of 2 subunits, type I and type II receptors (TβRI, TβRII). Both receptors are transmembrane serine/threonine kinases, and TβRII is bound by a specific ligand TGFβ, and constitutively activates TβRI, which mediates the signal to Smads. Recently it has been shown that signaling of TGFβ is involved in MAPK such as p44/p42 and p38, and JNK.

Although TGFβ is normally expressed in Kupffer cell, endothelial cells, and stellate cells, it is not expressed in normal cholangiocytes. However, TGFβ can be detected in cholangiocytes following BDL along with increased expression of M6P/IGF-II, an activator of latent TGFβ.²¹ TGFβ inhibits proliferation in human cholangiocytes. The growth-inhibitory effect of TGFβ has been shown in animal models in which atypical ductular proliferation caused by 3,5-diethoxycarbonyl-1,4-dihydrocollidine was inhibited in TGFβ 1 transfected mice.²² We have shown that TGFβ inhibits growth of nonmalignant human H69 cholangiocytes.²³ Growth inhibition by TGFβ may result from aberrant cell cycle progression. Transcriptional regulation by Smads results in altered expression of cyclin-dependent kinase (CDK) inhibitors such as p15INK4B, p21CIP1/WAF1 and suppression of cell cycle regulators CDK4, Cdc25A and c-Myc. We have also shown an increase in the p27 cyclin dependent kinase inhibitor due to inhibition of proteasomal regulation by TGFβ in human H69 cholangiocytes.²⁴ In the human cholangiocarcinoma cell line HuCCT1, TGFβ suppressed proliferation through regulation of the p21 cyclin dependent kinase inhibitor.²⁵

Altered TGFβ signaling has been demonstrated in many tumors including cholangiocarcinoma.¹⁹^,²⁰^,²⁶ Aberrant signaling may result from receptor mutations such as deletion of TβR1 or in alterations in intracellular signaling mediators such as smad4.²⁰^,²⁶^-²⁸ Altered TGFβ signaling may facilitate progression of tumor, allowing cells to escape from inhibitory effects of TGFβ.

The effects of TGFβ on cholangiocyte proliferation may be mediated indirectly through matrix-cell interactions since this cytokine is a potent mediator of the stromal reaction. Bile duct cancer is often accompanied by abundant fibrous stroma. Expression of TGFβ1 in biliary tract cancer cells correlates with collagen type I expression.²⁹ Yazumi et al. reported that three of five bile duct carcinoma cell lines had disruption of TGFβ signaling including the loss of Smad 4 expression and the heterozygous deletion of TβRII.²⁶ In these cases, abundant interstitial fibrosis was found in xenograft of TGFβ resistant cells, but not of TGFβ sensitive tumor suggesting that deregulated TGFβ signaling may also correlate with stromal cell reaction during tumor cell invasion.

Future Directions

Most information about the role of cytokines in cell growth is from cell lineages of the immune system, and cytokine regulation of biliary epithelial cell proliferation is poorly understood. The physiological repertoire of cytokines secreted by cholangiocytes and alterations during pathophysiological states are unknown. Furthermore, specific information regarding the characterization of the sites of cytokine production and regulation, structure and binding characteristics of cytokine receptors and the signal transduction sequence elicited by the receptor remain to be elucidated for several cytokines for which there is emerging evidence of a role in tissue homeostasis. In addition, the biological consequences, including altered expression of target genes, and the feedback loops terminating the cytokine response are poorly understood. These are attractive areas of investigation because improved understanding of the role played by cytokines during biliary epithelial growth will have major implications for therapeutic interventions for dysregulated growth during hepatic injury, disease or tumorigenesis.

Acknowledgements

Studies have been supported in part by a research fellowship from the American Association for the Study of Liver Diseases (Dr. Yamagiwa) and by grants from the National Institutes of Health (Grants DK60637 and DK02468) (Dr. Patel).

References

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Yamagiwa Y, Patel T. Cytokine Regulation of Cholangiocyte Growth. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

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Background
Cytokines and Biliary Epithelia
Cytokine Mediated Growth Regulation in Pathophysiological Processes
Cytokine Regulation of Biliary Epithelial Proliferation
Future Directions
Acknowledgements
References

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Madame Curie Bioscience Database [Internet].

Cytokine Regulation of Cholangiocyte Growth

Background

Cytokines and Biliary Epithelia

Figure 1

Cytokine Mediated Growth Regulation in Pathophysiological Processes

Hepatic Regeneration

Systemic Inflammation

Biliary Tract Inflammation

Tumor Cell Growth

Cytokine Regulation of Biliary Epithelial Proliferation

Interleukin-6

Figure 2

Transforming Growth Factor-beta (TGF βββββ)

Future Directions

Acknowledgements

References

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