IL-10 signalling and regulation

Explore the complexities of Interleukin-10 (IL-10) signaling and regulation, a crucial aspect in immune response modulation and its dual roles in cancer development and therapy.

1. Interleukin-10 (IL-10) is an anti-inflammatory cytokine expressed in many immune cells.
2. IL-10 signals via the JAK/STAT pathway, modulating inflammation and immune responses.
3. It plays a dual role in cancer, both inhibiting and promoting tumor development.
4. IL-10's effects on TILs, MHC-II downregulation, and STAT3 phosphorylation are key in cancer immunity.
5. Therapeutic strategies targeting IL-10 or its receptor show promise but require careful consideration due to potential side effects.

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 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 STAT1, STAT3 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).

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).

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.

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