Interleukin-6 (IL-6) plays important roles in the acute phase reaction, inflammation, hematopoiesis, bone metabolism, and cancer progression [1 - 5]. Mature mouse IL-6 is 187 amino acids (aa) in length and shares 39% and 85% aa sequence identity with human and rat IL-6, respectively [6 - 8]. IL-6 induces signaling through a cell surface heterodimeric receptor complex composed of a ligand binding subunit (IL-6 R alpha) and a signal transducing subunit (gp130). IL-6 binds to IL-6 R alpha, triggering IL-6 R alpha association with gp130 and gp130 dimerization [9]. Soluble forms of IL-6 R alpha are generated by both alternative splicing and proteolytic cleavage [5]. 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 [5]. 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, 5]. 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 - 5]. When dysregulated, it contributes to chronic inflammation in obesity, insulin resistance, inflammatory bowel disease, arthritis, sepsis, and atherosclerosis [1, 2, 5]. IL-6 can also function as an anti-inflammatory molecule, as in skeletal muscle where it is secreted in responseto exercise [2]. In addition, it enhances hematopoietic stem cell proliferation and the differentiation of Th17 cells, memory B cells, and plasma cells [1, 10].
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