Interleukin-6 receptor complex – Janus kinase-Signal transducer and activator of transcription pathway (IL-6R/JAK/STAT pathway)

The Interleukin-6 (IL-6) receptor complex – Janus kinase (JAK)-Signal transducer and activator of transcription (STAT) pathway is a central signaling axis governing the inflammatory response and immune homeostasis. Signaling begins when the cytokine IL-6 binds to the IL-6 receptor (IL-6R), which then triggers the dimerization of the signal-transducing glycoprotein 130 (gp130) (Tanaka et al., 2014, Cold Spring Harb Perspect Biol). This hexameric complex activates associated Janus kinases (JAK1, JAK2, and TYK2), which phosphorylate the cytoplasmic tail of gp130, creating docking sites for STAT3 (Wang et al., 2019, JAK-STAT Signaling). Once phosphorylated by JAKs, STAT3 dimerizes and translocates to the nucleus to drive the transcription of genes involved in the acute phase response, T-cell differentiation, and cell survival (Kishimoto, 2010, Annu Rev Immunol). Dysregulation of this pathway is a primary driver of chronic autoimmune diseases like rheumatoid arthritis and acute conditions such as cytokine release syndrome (NIH, 2023). Therapeutic strategies targeting this pathway include monoclonal antibodies that block the IL-6R (e.g., tocilizumab) or the IL-6 ligand (e.g., siltuximab), as well as small-molecule inhibitors of the JAK enzymes (e.g., baricitinib, upadacitinib) (Choy, 2015, Rheumatology).

Other names

IL-6/gp130/JAK/STAT signaling axisIL-6 signaling pathwayInterleukin-6 receptor signaling complexIL-6/STAT3 pathway

Inhibition of the signaling cascade through competitive antagonism of the IL-6 receptor, neutralization of the IL-6 ligand, or small-molecule inhibition of Janus kinase (JAK) enzymatic activity to prevent STAT protein phosphorylation and subsequent nuclear translocation.