Interleukin 6 (IL-6), also known as interferon-beta 2, 26 kDa protein and B cell stimulatory factor-2 (BSF-2), is a pleiotropic α-helical cytokine that plays important roles in acute phase reactions, inflammation, hematopoiesis, bone metabolism, and cancer progression. IL-6 activity is essential for the transition from acute inflammation to either acquired immunity or chronic inflammatory disease. It is secreted by multiple cell types as a 22 kDa - 28 kDa phosphorylated and variably glycosylated molecule. Mature human IL-6 is 183 amino acids (aa) in length and shares 41% aa sequence identity with mouse and rat IL-6. Alternate splicing generates several isoforms with internal deletions, some of which exhibit antagonistic properties.
IL-6 induces signaling through a cell surface heterodimeric receptor complex composed of a ligand binding subunit (IL-6 R) and a signal transducing subunit (gp130). IL-6 binds to IL-6 R, triggering IL-6 R association with gp130 and gp130 dimerization. gp130 is also a component of the receptors for CLC, CNTF, CT-1, IL-11, IL-27, LIF, and OSM. Soluble forms of IL-6 R are generated by both alternate splicing and proteolytic cleavage. In a mechanism known as trans-signaling, complexes of soluble IL-6 and IL-6 R elicit responses from gp130-expressing cells that lack cell surface IL-6 R. Trans-signaling enables a wider range of cell types to respond to IL-6, as the expression of gp130 is ubiquitous, while that of IL-6 R is predominantly restricted to hepatocytes, leukocytes, and lymphocytes. Soluble splice forms of gp130 block trans-signaling from IL-6/IL-6 R but not from other cytokines that utilize gp130 as a coreceptor.