Immune response - IL-17 signaling pathways

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IL-17 signaling pathway

The Interleukin-17 family consists of six cytokines in mammals. Among them, Interleukin 17A (IL-17) and Interleukin 17F (IL-17F) are produced by a distinct subset of CD4+ T helper (Th) cells called Th17 cells. IL-17 and IL-17F play a critical role in inflammation and pathogenesis of multiple autoimmune diseases [1], [2], [3], [4], [5].

Development and differentiation of Th17 cells requires a complex network of cytokines. In humans, Th17 differentiation is mediated by IL-23 and IL-6 released from myeloid dendritic cells, IL-1 beta and IL-6 derived from macrophages, as well as IL-21 produced by activated T cells [1], [6]. IL-17 released from Th17 cells affects different cell populations of the inflamed tissue, including fibroblasts, chondrocytes, osteoblasts, mast cells, neutrophils, airway epithelial cells and vascular endothelial cells [1], [7].

IL-17 acts through the Interleukin 17 receptor A (IL-17 receptor), which associates with Interleukin 17 receptor C (IL-17RC) to form a multimeric receptor complex [8]. IL-17RC binds both IL-17F and IL-17 [9]. Much is known regarding IL-17, but the understanding of IL-17 receptor signal transduction is still limited [10].

IL-17 receptor signaling induces activation of Nuclear factor kappa-B (NF-kB), Mitogen-activated protein kinase 3 and 1 (ERK1/2) and CCAAT-enhancer-binding proteins (C/EBPbeta and C/EBPdelta) followed by subsequent transcription of IL-17 target genes involved in inflammation and autoimmunity [1].

Among the main IL-17 target genes are: IL-6, which mediates inflammation and reinforces Th17 development; granulopoietic growth factors, such as Granulocyte colony-stimulating factor (G-CSF) and Granulocyte-macrophage colony-stimulating factor (GM-CSF); neutrophil-attracting CXC chemokines, such as CXCL1 chemokine ligand 1 (GRO-1), CXCL5 chemokine ligand 5 (ENA-78), CXCL6 chemokine ligand 6 (GCP2) and Interleukin 8 (IL-8); CC chemokines, such as CCL2, CCL7 and CCL20; Beta-defensin 2 (both CCL20 and Beta-defensin 2, which have antimicrobial activity and chemotactic activity to CCR6-positive dendritic and T cells [11], [12], [13]); the acute phase protein Lipocalin 2 (NGAL), which exhibits antibacterial activity; Intercellular adhesion molecule 1 (ICAM1); Prostaglandin-endoperoxide synthase 2 (COX-2), which catalyzes the biosynthesis of Prostaglandin E2 (PGE2), the mediator for pain and fever during inflammation; Nitric oxide synthase 2 (iNOS), which generates Nitric oxide (NO) during inflammation; mucus/gel-forming mucins, Mucin 5AC and Mucin 5B, which are secreted by airway cells (mucins contribute to mucociliary defense, but mucin overproduction leads to airway obstruction by mucus in chronic airway diseases, such as asthma and cystic fibrosis [14]); Tumor necrosis factor (ligand) superfamily, member 11 (RANKL), which promotes osteoclastogenesis and subsequent bone destruction in autoimmune diseases such as rheumatoid arthritis; and matrix metalloproteinases, such as MMP-1, MMP-3 (Stromelysin-1) and MMP-9, the major players in matrix destruction and tissue damage in arthritis [3], [10].

After stimulation with IL-17, TRAF3 interacting protein 2 (CIKS) is recruited to IL-17 receptor and triggers the activation of the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6), Mitogen-activated protein kinase kinase kinase 7 (TAK1) and Mitogen-activated protein kinase kinase kinase 14 (NIK(MAP3K14)) followed by downstream activation of transcription factor NF-kB [3], [15], [16], [17], [18].

Most IL-17-regulated genes contain crucial NF-kB sites in their promoters [10], [19]. However, IL-17 induces NF-kB activation only weakly. NF-kB can play an important but poorly understood role in controlling IL-17 target genes [20]. The transcription factors C/EBPbeta and C/EBPdelta are also responsible for cooperative enhancement of the promoters of IL-17 target genes [17], [19], [20], [21]. The upstream events that regulate C/EBPbeta and C/EBPdelta activation are poorly understood. C/EBPbeta and C/EBPdelta expression and activities are regulated by both transcriptional and posttranscriptional events. IL-17 has been found to up-regulate expression of C/EBPbeta and C/EBPdelta [17], [20], [21]. Their expression is dependent on CIKS, the NF-kB upstream activator in IL-17 receptor signaling [22]. IL-17 signaling can also regulate C/EBPbeta activity and subsequent expression of pro-inflammatory genes. The phosphorylation of two sites in the regulatory domains of C/EBPbeta by ERK1/2 and Glycogen synthase kinase 3 beta (GSK3 beta) inhibits C/EBPbeta activity [23].

IL-17 also activates Janus kinase 1 and 2 (JAK1 and JAK2) signaling [12], [24]. In human airway epithelial cells, IL-17 induces a JAK1/JAK2-associated Phosphoinositide-3-kinase (PI3K) signaling pathway independent from NF-kB activation. JAK1/JAK2 / PI3K reg class IA / PI3K cat class IA signaling results in an increase in lipid Phosphatidylinositol (3,4,5) (PtdIns(3,4,5)P3) and activation of V-akt murine thymoma viral oncogene homolog (AKT(PKB)) that, in turn, phosphorylates and inactivates GSK3 beta [18].

IL-17 also induces the phosphorylation and activation of mitogen-activated protein kinases MEK1 and MEK2, MEK3 and MEK6, and p38 MAPK. MEK1 and MEK2 can directly phosphorylate ERK1/2 and activate its signaling pathway, whereas MEK3 and MEK6 can phosphorylate and activate p38 MAPK [25]. p38 MAPK increases mRNA stability of multiple IL-17-induced transcripts, e.g. COX-2 [10].

In the airway epithelium, both IL-6 and IL-17 are involved in the expression of mucin genes, Mucin 5AC and Mucin 5B [26], [27]. Because IL-17 signaling results in the induction of IL-6, mucin expression is at least partly up-regulated by IL-17 through IL-6 by an autocrine/paracrine loop [26]. Expression of Mucin 5AC and Mucin 5B in response to IL-17 has been proposed to depend on ERK1/2 or JAK2/ ERK1/2 signaling [26], [27]. Several transcription factors such as c-Jun/c-Fos and SP1 can be involved in Mucin 5AC and Mucin 5B transcription [14], [28].



References

  1. Paunovic V, Carroll HP, Vandenbroeck K, Gadina M
    Signalling, inflammation and arthritis: crossed signals: the role of interleukin (IL)-12, -17, -23 and -27 in autoimmunity. Rheumatology (Oxford, England) 2008 Jun;47(6):771-6
  2. Ouyang W, Kolls JK, Zheng Y
    The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 2008 Apr;28(4):454-67
  3. Gaffen SL
    An overview of IL-17 function and signaling. Cytokine 2008 Sep;43(3):402-7
  4. Dong C
    Regulation and pro-inflammatory function of interleukin-17 family cytokines. Immunological reviews 2008 Dec;226:80-6
  5. Dubin PJ, Kolls JK
    Th17 cytokines and mucosal immunity. Immunological reviews 2008 Dec;226:160-71
  6. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F
    Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nature immunology 2007 Sep;8(9):942-9
  7. Dubin PJ, McAllister F, Kolls JK
    Is cystic fibrosis a TH17 disease? Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2007 Jun;56(6):221-7
  8. Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry J, Tocker J, Peschon J
    Cutting edge: interleukin 17 signals through a heteromeric receptor complex. Journal of immunology (Baltimore, Md. : 1950) 2006 Jul 1;177(1):36-9
  9. Kuestner RE, Taft DW, Haran A, Brandt CS, Brender T, Lum K, Harder B, Okada S, Ostrander CD, Kreindler JL, Aujla SJ, Reardon B, Moore M, Shea P, Schreckhise R, Bukowski TR, Presnell S, Guerra-Lewis P, Parrish-Novak J, Ellsworth JL, Jaspers S, Lewis KE, Appleby M, Kolls JK, Rixon M, West JW, Gao Z, Levin SD
    Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F. Journal of immunology (Baltimore, Md. : 1950) 2007 Oct 15;179(8):5462-73
  10. Shen F, Gaffen SL
    Structure-function relationships in the IL-17 receptor: implications for signal transduction and therapy. Cytokine 2008 Feb;41(2):92-104
  11. Schutyser E, Struyf S, Van Damme J
    The CC chemokine CCL20 and its receptor CCR6. Cytokine & growth factor reviews 2003 Oct;14(5):409-26
  12. Kao CY, Chen Y, Thai P, Wachi S, Huang F, Kim C, Harper RW, Wu R
    IL-17 markedly up-regulates beta-defensin-2 expression in human airway epithelium via JAK and NF-kappaB signaling pathways. Journal of immunology (Baltimore, Md. : 1950) 2004 Sep 1;173(5):3482-91
  13. Kao CY, Huang F, Chen Y, Thai P, Wachi S, Kim C, Tam L, Wu R
    Up-regulation of CC chemokine ligand 20 expression in human airway epithelium by IL-17 through a JAK-independent but MEK/NF-kappaB-dependent signaling pathway. Journal of immunology (Baltimore, Md. : 1950) 2005 Nov 15;175(10):6676-85
  14. Rose MC, Voynow JA
    Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiological reviews 2006 Jan;86(1):245-78
  15. Awane M, Andres PG, Li DJ, Reinecker HC
    NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells. Journal of immunology (Baltimore, Md. : 1950) 1999 May 1;162(9):5337-44
  16. Qian Y, Liu C, Hartupee J, Altuntas CZ, Gulen MF, Jane-Wit D, Xiao J, Lu Y, Giltiay N, Liu J, Kordula T, Zhang QW, Vallance B, Swaidani S, Aronica M, Tuohy VK, Hamilton T, Li X
    The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nature immunology 2007 Mar;8(3):247-56
  17. Maitra A, Shen F, Hanel W, Mossman K, Tocker J, Swart D, Gaffen SL
    Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression. Proceedings of the National Academy of Sciences of the United States of America 2007 May 1;104(18):7506-11
  18. Huang F, Kao CY, Wachi S, Thai P, Ryu J, Wu R
    Requirement for both JAK-mediated PI3K signaling and ACT1/TRAF6/TAK1-dependent NF-kappaB activation by IL-17A in enhancing cytokine expression in human airway epithelial cells. Journal of immunology (Baltimore, Md. : 1950) 2007 Nov 15;179(10):6504-13
  19. Shen F, Hu Z, Goswami J, Gaffen SL
    Identification of common transcriptional regulatory elements in interleukin-17 target genes. The Journal of biological chemistry 2006 Aug 25;281(34):24138-48
  20. Shen F, Ruddy MJ, Plamondon P, Gaffen SL
    Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-alpha-induced genes in bone cells. Journal of leukocyte biology 2005 Mar;77(3):388-99
  21. Ruddy MJ, Wong GC, Liu XK, Yamamoto H, Kasayama S, Kirkwood KL, Gaffen SL
    Functional cooperation between interleukin-17 and tumor necrosis factor-alpha is mediated by CCAAT/enhancer-binding protein family members. The Journal of biological chemistry 2004 Jan 23;279(4):2559-67
  22. Chang SH, Park H, Dong C
    Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. The Journal of biological chemistry 2006 Nov 24;281(47):35603-7
  23. Shen F, Li N, Gade P, Kalvakolanu DV, Weibley T, Doble B, Woodgett JR, Wood TD, Gaffen SL
    IL-17 receptor signaling inhibits C/EBPbeta by sequential phosphorylation of the regulatory 2 domain. Science signaling 2009 Feb 24;2(59):ra8
  24. Subramaniam SV, Cooper RS, Adunyah SE
    Evidence for the involvement of JAK/STAT pathway in the signaling mechanism of interleukin-17. Biochemical and biophysical research communications 1999 Aug 19;262(1):14-9
  25. Martel-Pelletier J, Mineau F, Jovanovic D, Di Battista JA, Pelletier JP
    Mitogen-activated protein kinase and nuclear factor kappaB together regulate interleukin-17-induced nitric oxide production in human osteoarthritic chondrocytes: possible role of transactivating factor mitogen-activated protein kinase-activated proten kinase (MAPKAPK). Arthritis and rheumatism 1999 Nov;42(11):2399-409
  26. Chen Y, Thai P, Zhao YH, Ho YS, DeSouza MM, Wu R
    Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. The Journal of biological chemistry 2003 May 9;278(19):17036-43
  27. Inoue D, Numasaki M, Watanabe M, Kubo H, Sasaki T, Yasuda H, Yamaya M, Sasaki H
    IL-17A promotes the growth of airway epithelial cells through ERK-dependent signaling pathway. Biochemical and biophysical research communications 2006 Sep 8;347(4):852-8
  28. Voynow JA, Gendler SJ, Rose MC
    Regulation of mucin genes in chronic inflammatory airway diseases. American journal of respiratory cell and molecular biology 2006 Jun;34(6):661-5

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