Interleukin-6 (IL-6) is a multifunctional α-helical cytokine that regulates cell growth and differentiation of various tissues [1, 2]. Mature human IL-6 is 183 amino acids in length and shares 39% sequence identity with mouse and rat IL-6 [3]. Alternative splicing generates several isoforms with internal deletions, some of which exhibit antagonistic properties [4-7]. IL-6 induces signaling through a cell surface heterodimeric receptor complex composed of a ligand binding subunit (IL-6R alpha) and a signal transducing subunit (gp130). IL-6 binds to IL-6R alpha, triggering IL-6R alpha association with gp130 [8]. gp130 is also a component of the receptors for CLC, CNTF, CT-1, IL-11, IL-27, LIF, and OSM [9]. Soluble forms of IL-6 R alpha are generated by both alternative splicing and proteolytic cleavage [2]. In a mechanism known as trans-signaling, complexes of soluble IL-6 and IL-6 R alpha elicit responses from gp130 -expressing cells that lack cell surface IL-6 R alpha [2]. 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 alpha is predominantly restricted to hepatocytes, monocytes, and resting lymphocytes [2]. Soluble splice forms of gp130 block trans-signaling from IL-6/IL-6 R alpha but not from other cytokines that use gp130 as a co-receptor [2, 10]. IL-6, along with TNF-alpha and IL-1, drives the acute inflammatory response and the transition from acute inflammation to either acquired immunity or chronic inflammatory disease [1, 2]. When dysregulated, it contributes to chronic inflammation in obesity, insulin resistance, inflammatory bowel disease, arthritis, sepsis, and atherosclerosis [1, 2, 5].
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