Inflammatory cytokines interleukin-6 and tumor necrosis factor alpha signaling pathway (IL-6/TNF-α pathway)

The "IL-6/TNF-α pathway" refers to the interconnected signaling networks involving the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Both cytokines are major regulators of immune and inflammatory responses and are implicated in the pathogenesis of multiple acute and chronic diseases, including autoimmune disorders, cancer, cardiovascular conditions, and severe infections. IL-6 predominantly signals through binding to the IL-6 receptor (IL-6R) and gp130, activating JAK/STAT and other pathways. TNF-α exerts its effects primarily through TNF receptors (TNFR1, TNFR2), activating the NF-κB pathway and orchestrating inflammatory gene transcription. Both cytokines not only mediate local and systemic inflammatory responses but also interact with each other's expression and signaling. As a pathway, their dysregulation is a therapeutic target, with approved monoclonal antibodies blocking either the cytokines or their receptors to treat conditions characterized by excessive or chronic inflammation. However, their pleiotropic roles in host defense mean that targeted inhibition can lead to increased risk of infection and other immune-related side effects.

Other names

IL-6 and TNF-α pathwayInterleukin-6 and tumor necrosis factor alpha pathwayPro-inflammatory cytokine pathwayInflammatory cytokine signaling axis

Monoclonal antibodies or receptor antagonists bind to IL-6 or its receptor, blocking downstream JAK/STAT signaling and suppressing pro-inflammatory activity. Monoclonal antibodies or fusion proteins bind to TNF-α or its receptor, preventing TNF-α-induced activation of the NF-κB pathway and downstream inflammatory and cytotoxic effects.