IL-6 Family Proteins

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IL-6 Family Proteins

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IL-6 Family Proteins Background

IL-6 is a 21-28 kDa glycoprotein that is produced and secreted by activated monocytes/macrophages, lymphocytes, endothelial cells, VSMCs, fibroblasts, and a host of other cells. There are two ways IL-6 initiates intracellular signaling. The classic pathway starts with binding of IL-6 to its receptor α-subunit, IL-6Rα, on cell membranes and subsequent recruitment of gp130, a separate transmembrane protein, to form an active hexameric signaling complex. The second mechanism, called the trans-signaling pathway, allows for cells not expressing the IL-6 receptor to respond to IL-6. In the trans-signaling pathway, IL-6 binds to its soluble receptor, IL-6Rα, which is a cleavage produce of the membrane bound IL-6Rα, and that complex then associates with gp130. Downstream of both pathways, gp130-associated tyrosine kinases (JAKs-1 and Tyk 2 kinases) are then recruited to tyrosine-phosphorylate gp130. That leads to recruitment of cytoplasmic transcription factors Signal Transducer and Activator of Transcription (STAT1 and STAT3) that bind to gp130 via their src homology-2 (SH2) domains. The STATs are then phosphorylated at Tyr705 by the JAK/Tyk kinases, allowing them to homo- or hetero-dimerize and translocate into the nucleus where STATs bind to target genes like C-reactive protein (CRP), fibrinogen, and angiotensinogen to enhance their transcription. Although the Ras-ERK-MAPK pathway also can be initiated by IL-6, that pathway plays a minor role compared to the Jak/STAT pathway. Since gp130 is ubiquitously expressed, almost any cell can respond to IL-6 via the trans-signaling pathway.

IL-6 has multiple biological activities. It can induce differentiation of B-cells and growth of plasma cells, activate T-cells, stimulate production of platelets and acute-phase response proteins in the liver, cause proliferation of VSMCs in conjunction with platelet-derived growth factor (PDGF), and help recruit leukocytes into areas of inflammation. In vitro, IL-6 can directly induce monocytes to differentiate into macrophages and upregulate CD36 on their surface. Moreover, MCP-1 is induced by the IL-6 Jak/STAT pathway in cultured peripheral blood mononuclear cells and VSMCs. Endothelial cells do not express IL-6R, but studies have shown that they can be stimulated in vitro by IL-6 via the trans-signaling pathway to upregulate proteins such as ICAM-1 to help leukocytes such as monocyte and T-cells that express the surface αmβ2 integrin Mac-1 (CD11b/CD18) to bind. Recent studies have shown that trans-signaling is required for Ang II-dependent hypertension and for recruitment of mononuclear cells into sites of inflammation. Recruitment of T-lymphocytes into the vascular wall has been shown to cause Ang II-dependent hypertension. Together these results suggest that Ang II-induced IL-6, via trans-signaling, mediates T-cell recruitment leading to hypertension. Moreover, they suggest that MCP-1 might be the chemokine induced by IL-6 that actually recruits T-cells.

IL-6 is highly upregulated in patients with atherosclerotic cardiovascular diseases. There is increased IL-6 in atherosclerotic tissue, primarily in macrophages and, to a lesser degree, VSMCs. IL-6 also has been shown to colocalize with AT1, ACE, and Ang II in macrophages around the site of plaque rupture in coronary arteries from patients with myocardial infarction. Multiple clinical studies have shown that patients with unstable angina have high levels of plasma IL-6 and are at increased risk for plaque rupture leading to an acute myocardial infarction (MI). People without clinical evidence of heart disease, but with IL-6 levels in the upper quartile of the normal range are at increased risk of future MI and cardiovascular mortality as well as all-cause mortality. Furthermore, elevated IL-6 has been associated with increased mortality regardless of cardiovascular disease severity. There are similar findings with CRP, which is produced by cells such as hepatocytes following IL-6 stimulation.

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