IL6

Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a central role in immune regulation, inflammation, and hematopoiesis. It is produced by a variety of cells, including macrophages, T cells, dendritic cells, fibroblasts, endothelial cells, and adipocytes, in response to infection, injury, or stress. IL-6 acts on many cell types to coordinate the acute phase response and mobilize adaptive immunity.

IL-6 signals through a receptor complex consisting of the IL-6 receptor (IL-6R) and the signal transducer gp130. Two signaling modes exist: classical signaling, where IL-6 binds membrane-bound IL-6R on limited cell types; and trans-signaling, where IL-6 binds a soluble IL-6R enabling activity on cells that lack membrane IL-6R. Signal transduction primarily uses the JAK/STAT pathway, notably STAT3, but also engages MAPK and PI3K pathways.

Physiologically, IL-6 induces hepatic production of acute-phase proteins such as C-reactive protein and fibrinogen, promotes hepcidin expression affecting iron metabolism, supports B cell differentiation into plasma cells, and influences T cell subsets, including Th17 differentiation in concert with TGF-β. It also contributes to fever and metabolic regulation during inflammation.

Dysregulated IL-6 signaling is associated with chronic inflammatory and autoimmune diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, Castleman disease) and contributes to cancer progression and cachexia. It has a prominent role in hyperinflammatory states such as cytokine storms seen in severe infections, including COVID-19.

Therapeutically, IL-6 pathway inhibition is achieved with antibodies against IL-6 or IL-6R (for example, siltuximab targets IL-6, while tocilizumab and sarilumab target IL-6R). JAK inhibitors can also dampen IL-6 signaling indirectly.