Interleukin-6 (IL-6) is an important pro-inflammatory cytokine released during infection or tissue damage to promote innate and adaptive immune responses. IL-6 is rapidly expressed by cells of the innate immune system, such as macrophages, upon encountering damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) as part of the host defense strategy to eliminate infected cells or damaged tissue. However, excessive IL-6 production can lead to the development of chronic inflammatory diseases (such as rheumatoid arthritis) and cytokine storms, seen in patients undergoing CAR-T therapy or experiencing diseases like COVID-19 caused by the SARS-CoV-2 virus.
IL-6 is a member of the pro-inflammatory cytokine family, with a protein structure composed of four long α-helices, including two GP130 binding sites and one IL-6Rα binding site. IL-6 can activate signaling pathways by binding to membrane-bound IL-6R (mIL-6R) or circulating soluble IL-6R (sIL-6R) in combination with the glycoprotein gp130, thus initiating its pleiotropic effects. The pleiotropy of IL-6 is related to the ubiquitous expression of gp130, while IL-6R expression is limited to a few cell types, including lymphocytes, monocytes/macrophages, and hepatocytes. IL-6 exerts its effects through three different signal transduction pathways: classical signaling, trans-signaling, and trans-presentation. In classical signaling, IL-6 binds to the complex formed by mIL-6R and gp130, leading to signal transduction via the activation of the JAK-STAT3 pathway. In trans-signaling, IL-6 binds to sIL-6R present in serum and tissue fluids. In trans-presentation, dendritic cells presenting IL-6 bound to mIL-6R to T cells expressing gp130 on their surface. This alternate action of IL-6 signaling is a crucial event in initiating the differentiation of Th17 helper T cells.
