Interleukin-10 signaling axis (IL-10 axis)

The Interleukin-10 (IL-10) signaling axis is a fundamental regulatory pathway in the immune system, primarily known for its potent anti-inflammatory and immunosuppressive effects (Ouyang & O'Garra, 2019). The axis is initiated when the IL-10 cytokine binds to its cognate receptor complex, a heterotetramer consisting of two IL-10RA and two IL-10RB subunits (Moore et al., 2001). This binding event activates the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, specifically involving JAK1, TYK2, and the transcription factor STAT3 (UniProt P22301). Once activated, STAT3 translocates to the nucleus to induce the expression of genes that inhibit the production of pro-inflammatory cytokines, such as TNF-alpha, IL-1, and IL-6, and downregulate MHC class II expression on antigen-presenting cells (Iyer & Cheng, 2012). Dysregulation of this axis is linked to various pathologies, including inflammatory bowel disease, where IL-10 deficiency leads to severe enterocolitis, and cancer, where IL-10 can facilitate tumor immune escape or, conversely, enhance CD8+ T-cell activity (Saraiva & O'Garra, 2010). Therapeutic interventions targeting this axis include recombinant IL-10 (Ilodecakin) and its pegylated form (Pegilodecakin) for chronic inflammation and oncology (Naing et al., 2019). Additionally, monoclonal antibodies and small molecules are being explored to either augment or inhibit this signaling depending on the disease context (Ouyang & O'Garra, 2019). The complexity of IL-10 signaling, particularly its dual role in cancer, presents both significant therapeutic opportunities and challenges in drug development.

Other names

IL-10 pathwayIL-10/IL-10R axisCytokine synthesis inhibitory factor signalingIL10-STAT3 axis

The mechanism involves the binding of the IL-10 homodimer to the IL-10RA/IL-10RB receptor complex, which triggers the activation of JAK1 and TYK2. These kinases phosphorylate STAT3, which then homodimerizes and translocates to the nucleus to bind to IL-10-responsive elements in the promoters of target genes. This results in the transcriptional upregulation of anti-inflammatory mediators and the suppression of pro-inflammatory cytokine genes (Ouyang & O'Garra, 2019; Moore et al., 2001).