IL-10 signalling and regulation

IL-10 signalling and regulation

IL-10 Overview

Interleukin-10 (IL-10), a 17-20 kDa homodimeric glycoprotein, is an anti-inflammatory cytokine that was originally identified in T helper 2 (Th2) cells and later discovered to be expressed by almost all immune cells, including T cells, B cells, macrophages, dendritic cells and granulocytes, and also by epithelial cells (Sabat et al, 2010; Jung et al, 2004). IL-10 is a potent anti-inflammatory mediator, and has an essential role in preventing inflammatory-linked pathologies by limiting inflammatory-induced damage to the host (Kuhn et al, 1993).

IL-10 Signalling and Regulation

IL-10 binds to the membrane-bound receptor IL-10R, which is a member of the IFN family of receptors. IL-10R has two subunits, an a and a b subunit, where the b subunit is ubiquitously expressed and the a subunit highly expressed on monocytes and macrophages (Gasche et al, 2003). IL-10 signals via the JAK/STAT pathway after ligation to IL-10R. The cytosolic tyrosine kinases Janus Kinase 1 (Jak1) and tyrosine kinase 2 (Tyk2) phosphorylate the cytoplasmic domain of the IL-10R leading to interactions with several signal transducer and activator of transcription proteins (STATs), primarily STAT1STAT3 and STAT5, and the subsequent nuclear translocation of STAT1 (Finbloom and Winestock, 1995). IL-10 signalling induces the activation of several transcription factors that upregulate multiple genes associated with pro-inflammatory inhibition, such as suppressor of cytokines 3 (SOCS3) which targets and inhibits JAK/STAT and MAPK signalling pathways in the cytosol, and anti-apoptotic genes, such as Bcl-2 and Bim (Verma et al, 2016; Niss et al, 2015; Weber-Nordt et al, 1996; Taga et al, 1994). Additionally, the pro-inflammatory cytokine IL-6 induces downstream signalling that competes with IL-10 signalling to de-phosphorylate STAT3 and induce a robust pro-inflammatory response, however, the effects of IL-6 are more transient that that of IL-10 (Braun et al, 2013; Niemand et al, 2003).

Il-10 can be induced in response to Toll-like receptor 2 and 4 (TLR2 and TLR4) activation, described mainly in cells of the innate immune response; dendritic cells and macrophages (Siewe et al, 2006; McGuirk et al, 2002). Optimal TLR-induced IL-10 production requires both of the cytosolic TLR adaptor proteins myeloid differentiation primary response gene (MyD88) and TIR-domain-containing adapter-inducing interferon-β(TRIF), indicating a role for Type I interferons, NF-Kappa Beta and mitogen-associated protein kinase (MAPK) in the transcription of IL-10 (Chang et al, 2007). Interestingly, IL-10 can drive its own signalling in an autocrine positive feedback loop facilitated by the IL-10 dependent induction of STAT3 (Moore et al, 2001). Studies have also demonstrated that the microRNA miR106a can regulate IL-10 degradation (Sharma et al, 2009).

The Role of IL-10 in Cancer

While it has been long established that while acute inflammation is protective in function, chronic inflammation leads to dysregulated cellular responses that are associated with the progression of multiple diseases, with several pro- and anti-inflammatory cytokines investigated as biomarkers for cancer prognoses. IL-10, along with another anti-inflammatory cytokine transforming growth factor beta (TGFb) (Feagins, 2010), has been associated with immune cell invasion into tumours, and serum levels of IL-10 have been shown to predict poor prognosis in cancer patients (Lech-Maranda et al, 2006), whereas the pro-inflammatory factors closely associated with tumorigeneses are TNFa (Bates and Mercurio, 2003) and IL-6 (Matsumoto et al, 2010). IL-10 has dual roles in cancer progression. IL-10 can inhibit NF-Kappa Beta activation, therefore limiting the transcription of pro-inflammatory cytokines and preventing tumour development (Lin and Karin, 2007; Schottelius et al, 1999). Additionally, Il-10 deficiency in mice leads to the development of colorectal cancer (CRC), phenotypically reflecting irritable bowel syndrome - associated CRC in humans (Sturlan et al, 2011).Conversely, elevated IL-10 levels produced by tumour-infiltrating lymphocytes (TILs) have been identified in several malignant cancer cases (Santin et al, 2001; Ortegal et al, 2000). As IL-10 signalling results in the sustained phosphorylation of STAT3, which leads to the suppression of chronic inflammation, it can exert a pro-tumourigenic response by both suppressing the immune response to ‘foreign’ cancerous cells, thus allowing cancer cells to evade protective immunosurveillance and allowing tumour immune invasion (Hamidullah et al, 2012), and by upregulated anti-apoptotic Bcl-2 proteins (Sredni et al, 2004; Alas et al, 2001). It has been demonstrated that IL-10 exerts its’ immunosuppressive effect by downregulating MHC-II molecules on macrophages and dendritic cells, leading to reduced antigen presentation (Hamidullah et al, 2012).

Targeting IL-10 as an Immunotherapeutic Strategy

The use of anti-10 receptor antibodies, effectively blocking IL-10 receptor ligation, as a co-therapeutic strategy leads to robust anti-tumour activity in mice (Vicari et al, 2002). Anti-10 receptor antibodies have also been successful in response to viral infection (Ejranes et al, 2006).

However, as il-10-deficient mice spontaneously develop intestinal inflammation and hepatic immunopathology (Gaddi et al, 2012; Oakley et al, 2008), much caution is to be taken in the develop of therapeutics using IL-10. Shortening the half-life of peptides targeting IL-10R may limit some of the side effects induced by inhibiting IL-10 signalling.

Figure 1: IL-10 signalling: IL10 binds the homodimeric membranous receptor IL-10R, leading to cytosolic associations with the tyrosine kinases JAK1 and Tyr2, which subsequently signal downstream to STAT1, inducing STAT1 phosphorylation. Nuclear translocation of phosphorylated STAT1 upregulates the transcription of multiple anti-apoptotic and immunosuppressive genes, such as SOCS3, which negatively feedback to limit JAK1 activation and MAPK signalling to NF-Kappa Beta.


Alas S, Emmanouilides C, Bonavida B. Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin's lymphoma to apoptosis. Clin Cancer Res. 2001. 7(3):709-23.

Bates RC, Mercurio AM. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell. 2003. 14(5):1790-800.

Braun DA, Fribourg M, Sealfon SC. Cytokine response is determined by duration of receptor and signal transducers and activators of transcription 3 (STAT3) activation. J Biol Chem. 2013. 288(5):2986-93.

Chang, E. Y., Guo, B., Doyle, S. E. & Cheng, G. Cutting edge: involvement of the type I IFN production and signaling pathway in lipopolysaccharide‐induced IL‐10 production. J. Immunol. 2007. 178, 6705–6709.

Ejrnaes M, Filippi CM, Martinic MM, Ling EM, Togher LM, Crotty S, von Herrath MG. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med. 2006. (11):2461-72.

Feagins LA. Role of transforming growth factor-β in inflammatory bowel disease and colitis-associated colon cancer. Inflamm Bowel Dis. 2010. 16(11):1963-8.

Finbloom DS, Winestock KD. IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes. J Immunol. 1995. 155(3):1079-90.

Gaddi PJ, Crane MJ, Kamanaka M, Flavell RA, Yap GS, Salazar-Mather TP. IL-10 mediated regulation of liver inflammation during acute murine cytomegalovirus infection. PLoS One. 2012. 7(8):e42850.

Gasche C, Grundtner P, Zwirn P, Reinisch W, Shaw SH, Zdanov A, Sarma U, Williams LM, Foxwell BM, Gangl A. Novel variants of the IL10 receptor 1 affect inhibition of monocyte TNF-alpha production. J Immunol. 2003. 170(11):5578-82.

Hamidullah, Changkija B, Konwar R. Role of interleukin-10 in breast cancer. Breast Cancer Res Treat. 2012. 133(1):11-21.

J Biol Chem. 1999. 274(45):31868-74.

Jung M, Sabat R, Krätzschmar J, Seidel H, Wolk K, Schönbein C, Schütt S, Friedrich M, Döcke WD, Asadullah K, Volk HD, Grütz G. Expression profiling of IL-10-regulated genes in human monocytes and peripheral blood mononuclear cells from psoriatic patients during IL-10 therapy. Eur J Immunol. 2004. 34(2):481-93.

Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993. 75(2):263-74.

Lech-Maranda E, Bienvenu J, Michallet AS, Houot R, Robak T, Coiffier B, Salles G. Elevated IL-10 plasma levels correlate with poor prognosis in diffuse large B-cell lymphoma. Eur Cytokine Netw. 2006. 17(1):60-6.

Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 2007. 117(5):1175-83.

McGuirk P, McCann C, Mills KH. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J Exp Med. 2002. 195(2):221-31.

Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001. 19:683-765.

Niemand C,Nimmesgern A,Haan S,Fischer P,Schaper F,Rossaint R,Heinrich PC,Muller-NewmanG.Activation of STAT3 by IL6 and IL10 in primary human macrophages is differentially modulated by suppressor of cytokine signaling 3. J Immunol. 2003. 170(6):3263-72.

Niss O, Sholl A, Bleesing JJ, Hildeman DA. IL10/Janus kinase/signal transducer and activator of transcription 3 signaling dysregulates Bim expression in autoimmune lymphoproliferative syndrome. J Allergy Clin Immunol. 2015. 135(3):762-70.

Oakley OR, Garvy BA, Humphreys S, Qureshi MH, Pomeroy C. Increased weight loss with reduced viral replication in interleukin-10 knock-out mice infected with murine cytomegalovirus. Clin Exp Immunol. 2008. 151(1):155-64.

Ortegel JW, Staren ED, Faber LP, Warren WH, Braun DP. Cytokine biosynthesis by tumor-infiltrating T lymphocytes from human non-small-cell lung carcinoma. Cancer Immunol Immunother. 2000. 48(11):627-34.

Sabat R, Grütz G, Warszawska K, Kirsch S, Witte E, Wolk K, Geginat J. Biology of interleukin-10. Cytokine Growth Factor Rev. 2010. 21(5):331-44.

Santin AD, Bellone S, Ravaggi A, Roman J, Smith CV, Pecorelli S, Cannon MJ, Parham GP. Increased levels of interleukin-10 and transforming growth factor-beta in the plasma and ascitic fluid of patients with advanced ovarian cancer. BJOG. 2001. 108(8):804-8.

Schottelius AJ, Mayo MW, Sartor RB, Baldwin AS Jr. Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding.

Sharma, A, Kumar M, Aich J, Hariharan M, Brahmachari SK, Agrawal A, Ghosh B. Posttranscriptional regulation of interleukin‐10 expression by hsa‐miR‐106a.

Proc. Natl Acad. Sci. USA. 2009. 106, 5761–576.

Siewe L, Bollati-Fogolin M, Wickenhauser C, Krieg T, Müller W, Roers A. Interleukin-10 derived from macrophages and/or neutrophils regulates the inflammatory response to LPS but not the response to CpG DNA. Eur J Immunol. 2006. 36(12):3248-55.

Sredni B, Weil M, Khomenok G, Lebenthal I, Teitz S, Mardor Y, Ram Z, Orenstein A, Kershenovich A, Michowiz S, Cohen YI, Rappaport ZH, Freidkin I, Albeck M, Longo DL, Kalechman Y. Ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) sensitizes tumors to chemotherapy by inhibiting the tumor interleukin 10 autocrine loop. Cancer Res. 2004. 64(5):1843-52.

Sturlan S, Oberhuber G, Beinhauer BG, Tichy B, Kappel S, Wang J, Rogy MA. Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development. Carcinogenesis. 2001. 22(4):665-71.

Taga K, Chretien J, Cherney B, Diaz L, Brown M, Tosato G. Interleukin-10 inhibits apoptotic cell death in infectious mononucleosis T cells. J Clin Invest. 1994. 94(1):251-60.

Verma R, Balakrishnan L, Sharma K, Khan AA, Advani J, Gowda H, Tripathy SP, Suar M, Pandey A, Gandotra S, Prasad TS, Shankar S. A network map of Interleukin-10 signaling pathway. J Cell Commun Signal. 2016. 10(1):61-7.

Vicari AP, Chiodoni C, Vaure C, Aït-Yahia S, Dercamp C, Matsos F, Reynard O, Taverne C, Merle P, Colombo MP, O'Garra A, Trinchieri G, Caux C. Reversal of tumor induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med. 2002. 196(4):541-9.

Weber-Nordt RM, Henschler R, Schott E, Wehinger J, Behringer D, Mertelsmann R, Finke J. Interleukin-10 increases Bcl-2 expression and survival in primary human CD34+ hematopoietic progenitor cells. Blood. 1996. 88(7):2549-58.

10th Jul 2020 Sinead Kinsella PhD

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