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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.
Holland-Frei Cancer Medicine. 6th edition.
Show detailsInterleukin-10
Interleukin-10 is an important immunoregulatory cytokine whose principal biologic function appears to involve the suppression of cytokine synthesis in the Th1 subset of CD41 T helper cells. Originally described as cytokine synthesis inhibitory factor, this 35-kDa noncovalently linked homodimeric peptide is produced by both Th1 and Th2 T cells, monocytes, B lymphocytes, and keratinocytes.166,167 The suppression by IL-10 of IL-2 and interferon-γ production by Th1 CD41 cells, and of IL-1, TNF, IL-6, IL-8, and colony-stimulating factors by monocytes, coupled with its ability to stimulate B-cell growth and immunoglobulin production suggest that IL-10 could find a therapeutic use in sepsis and a number of autoimmune diseases that are associated with inflammation. Indeed, therapy with this cytokine in animal models of sepsis results in improved survival.113,168,169 The suppressive effects of IL-10 on cell-mediated immunity suggest that it might find a role in transplant rejection or the treatment of graft-versus-host disease.170 In two Phase I trials of single bolus, intravenous doses of recombinant IL-10 administered to normal volunteers, no adverse side effects were noted, and a transient neutrophilia and monocytosis associated with significant lymphopenia, inhibition of T-cell proliferation, and dose-dependent inhibition of TNF-α and IL-1β production were also noted.171,172 IL-10 is expected to have great utility in regulation of autoimmune disease, for which suppression of the T-helper activity is desired.
Interleukin-13
Like IL-4 and IL-10, IL-13 is another cytokine that is produced by activated T cells that shares the capacity to inhibit cytokine synthesis by activated monocytes and modulates B-cell responses through its effects on the activation, proliferation, and differentiation of B cells.173,174
Interleukin-15
Interleukin-15 is a novel cytokine that, despite having no sequence homology with IL-2, binds with the β and γ components of the IL-2 receptor.175,176 IL-15 is expressed in a much wider range of tissues than IL-2, including activated monocytes and macrophages and skeletal muscle, kidney, and placenta. Similar to IL-2, IL-15 has been demonstrated to potentiate NK-cell cytokine production and cytotoxic activity; together with its production by monocytes and macrophages, these observations suggest that it may play a role in normal host immunity.177 Potential uses for IL-15 in cancer therapeutics are still being considered.
Interleukin-17
Interleukin-17 is a potent proinflammatory cytokine produced by activated memory T cells that was first identified as a rodent complementary deoxyribonucleic acid (cDNA) transcript, termed CTLA8.178 The biologic actions of IL-17 are increasing the local production of chemokines such as IL-8, monocyte chemoattractant protein-1 (MCP-1), and Groα, promoting the recruitment of monocytes and neutrophils.179 It also stimulates the production of the hematopoietic cytokines G-CSF and GM-CSF. IL-17 mediates its proinflammatory effects via its receptor, IL-17R, which is commonly expressed on all cell types. Bioactive IL-17 is detected in rheumatoid arthritis and osteoarthritis synovial fluid.180 The association of IL-17 with inflammation and the induction of other cytokines that regulate the inflammatory response suggest that there may be therapeutic use in the blocking of the function of those cytokines.
Interleukin-18
Interleukin-18 was first identified as an IFN-γ-inducing factor (IGIF) and is structurally related to IL-1 family.181 Many cell types have been reported to produce IL-18, including macrophages, dendritic cells, astrocytes, microglia, intestinal and airway epithelial cells, keratinocytes, and osteoblasts.182 Major targets of IL-18 include macrophages, NK cells, and T cells, and the major effect is the induction of cytokine synthesis such as IFN-γ from T cells and IL-13 from NK cells and T cells. As of today, evidence has accumulated that IL-18 plays a key role in protection against infectious disease and is a critical inducer of both innate and acquired immune responses.
Interleukin-19
Interleukin-19 is one of the members, as a homolog, of human IL-10 family of cytokines. IL-19 shares 21% amino acid identity with IL-10 and the exon/intron structure of IL-19 is similar to that of the human IL-10 gene, comprising five exons and four introns within the coding region of the IL-19 cDNA.183 The expression of IL-19 messenger ribonucleic acid (mRNA) can be induced in monocytes by lipopolysaccharide treatment and GM-CSF is the only known inducer of IL-19 gene expression in monocytes.
Interleukin-20
Interleukin-20 is discovered as another IL-10 related cytokine, which induces keratinocyte proliferation and causes aberrant epidermal differentiation in the skin.184 IL-20 receptor complex is described as a heterodimer of two orphan class II cytokine receptor subunits; named IL-20Rα and IL-20Rβ. Recombinant IL-20 binds to its receptor on keratinocytes and stimulates a STAT3-containing signal transduction pathway.185 Experimental evidence suggests a role for IL-20 and its receptor in psoriasis, which is a multigenic skin disease characterized by increased keratinocyte proliferation and differentiation. Clinical applications are currently under consideration.
Interleukin-22
Interleukin-22 was originally described as an IL-9-inducible gene and called IL-TIF.186 IL-22 activities include induction of the acute phase response in hepatocytes, and are mediated through a heterodimeric receptor composed of the IL-22R subunit and the β chain of IL-10R.187 In addition to its cellular receptor, IL-22 binds to a secreted class II cytokine receptor family members and acts as a natural IL-22 antagonist. To date, IL-22 has not been applied clinically.
Interleukin-24
Interleukin-24 was originally named melanoma differentiation-associated gene-7 (mda-7) when it was discovered in 1995, and identified by subtractive hybridization after the treatment of melanoma cells with IFN-β and mezerein, which caused their terminal differentiation and growth arrest.188 In 2001, it was realized that mda-7 encodes a secreted protein that exhibits significant homology to IL-10 as another member of the IL-10 family, and was officially designated as IL-24. Human IL-24 is secreted by activated peripheral blood mononuclear cells and is the ligand for two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2.189 IL-24 was earlier shown as tumor-suppressor gene and the protein product found to be constitutively expressed by melanocytes, nevus cells, and some primary melanomas, but not metastatic lesions of melanoma.190,191 Clinical trials with IL-24 protein are under consideration; however, at the time of writing this chapter, the gene transfer of an adenoviral vector containing mda-7/IL-24 is in Phase I gene therapy testing (Sunil Chada, Introgen Therapeutics, Inc., personal communication, November 2002). This is possibly the first example of a tumor-suppressor gene exhibiting immune stimulatory properties.
Interleukin-25
Interleukin-25 was recently (in 2001) identified as a cytokine that is structurally related to IL-17 and that induces IL-4, IL-5, and IL-13 gene expression.192 The induction of these cytokines results in Th2-like responses marked by increased serum IgE, IgG1, and IgA levels, blood eosinophilia, and epithelial cell hyperplasia. As a newly discovered cytokine, little is known about IL-25 besides that the cytokine, derived from Th2 T cells, is capable of amplifying allergic type inflammatory responses by its actions on other cells.
- Cytokines Considered for Clinical Application or in Early Trials - Holland-Frei ...Cytokines Considered for Clinical Application or in Early Trials - Holland-Frei Cancer Medicine
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