Interleukin-6 (IL-6)

Interleukin-6 (IL-6) is a small secreted signaling protein — a pleiotropic cytokine of roughly 21–28 kDa, depending on glycosylation — produced by a wide range of cell types including T cells, B cells, monocytes and macrophages, fibroblasts, endothelial cells, and adipocytes. It is one of the principal mediators of the acute phase response, driving hepatic production of C-reactive protein (CRP) and fibrinogen, and it also contributes to B-cell differentiation into antibody-secreting plasma cells, T-helper cell polarization (notably toward IL-17A–producing Th17 cells), hematopoiesis, and metabolic regulation. Its many historical names — B-cell stimulatory factor 2, hybridoma growth factor, interferon beta-2 — reflect the independent lines of research that converged on a single protein.

IL-6 signals through a receptor complex comprising the ligand-binding IL-6 receptor and the shared signal-transducing subunit gp130, engaging both classic signaling on cells expressing membrane-bound IL-6R and trans-Signaling via soluble IL-6R, which extends responsiveness to cells that lack the receptor and is generally associated with pro-inflammatory effects. Receptor engagement activates the JAK/STAT cascade, principally JAK2 and STAT3, alongside the RAS–MAPK and Phosphatidylinositol 3-kinase (PI3K)–Protein kinase B (PKB) pathways. IL-6 transcription is itself induced by upstream inflammatory signaling, including toll-like receptor 4 activation by lipopolysaccharide, NF-κB, and NLRP3 inflammasome–associated responses, placing it in a tightly coupled network with tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-18, and CXCL8. Because circulating IL-6 concentrations track systemic inflammation, the protein is widely used as a biomarker — in sepsis, traumatic brain injury, cardiovascular risk stratification, and chronic inflammatory and metabolic disease — and as a component of multi-analyte diagnostic panels. Sustained IL-6 signaling is implicated in rheumatoid arthritis and other autoimmune conditions, atherosclerosis, obesity-associated insulin resistance and type 2 diabetes, cytokine release syndromes including severe COVID-19, and tumor progression through STAT3-driven survival and angiogenic programs involving VEGFA. These roles have made the pathway a validated drug target: antibodies against IL-6 and its receptor, such as tocilizumab and siltuximab, are approved therapies, and JAK inhibitors block signaling downstream. IL-6 is also a recurrent hub node in network pharmacology analyses of anti-inflammatory natural products, including polyphenols and flavonoids such as quercetin, baicalein, and naringenin.