Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The G protein-coupled receptor G2A is highly expressed on macrophages and lymphocytes and has been localized to atherosclerotic plaques. We examined the role of G2A in modulating monocyte/endothelial interactions in the vessel wall. We measured adhesion of WEHI 78/24 monocytes to aortas of C57BL/6 (B6) and G2A-deficient (G2A(-/-)) mice using an ex vivo adhesion assay. G2A(-/-) mice had 10-fold elevations in adhesion of monocytes to aortas. Injection of GFP-expressing wild-type macrophages into B6 and G2A(-/-) mice in vivo showed increased macrophage accumulation in the aortic wall of G2A(-/-) mice. We isolated aortic endothelial cells (ECs) from B6 and G2A(-/-) mice and found a 2-fold increase in intercellular adhesion molecule-1 and E-selectin surface expression on G2A(-/-) ECs using flow cytometry. Using ELISA, we found a 3-fold increase in interleukin-6 and monocyte chemoattractant protein-1 production by G2A(-/-) ECs compared with B6 ECs. We found a dramatic increase in nuclear localization of the p65 subunit of nuclear factor kappaB in G2A(-/-) ECs. Transfection of G2A into G2A(-/-) ECs to restore normal expression levels reduced p65 nuclear localization to 35%. Restoration of G2A expression in G2A(-/-) ECs significantly reduced intercellular adhesion molecule-1 and endothelial selectin surface expression and reduced monocyte chemoattractant protein-1 and interleukin-6 production. Restoring G2A to G2A(-/-) ECs reduced monocyte adhesion by 80% compared with G2A(-/-) ECs in a flow chamber assay. Absence of G2A in endothelium results in proinflammatory signaling and increased monocyte/endothelial interactions in the aortic wall. Thus, endothelial G2A expression may aid in prevention of vascular inflammation and atherosclerosis.
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PMID:Absence of the G protein-coupled receptor G2A in mice promotes monocyte/endothelial interactions in aorta. 1733 35

G2A was identified as a G protein-coupled receptor that can be induced by different classes of DNA-damaging agents and block cell cycle progression in lymphocytes. We recently reported that G2A functions as a receptor for oxidized free fatty acids derived from linoleic and arachidonic acids. When ectopically expressed in CHO cells, G2A mediates intracellular signaling events such as intracellular calcium mobilization and JNK activation in response to oxidized free fatty acids. In human epidermal keratinocytes, G2A mediates the secretion of cytokines including interleukin-6 and -8, and blocks cell cycle progression at the G1 phase in response to ligands. G2A might function as a sensor that monitors the oxidative states and mediates appropriate cellular responses such as secretion of paracrine signals and attenuation of proliferation.
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PMID:G2A as a receptor for oxidized free fatty acids. 1906 86

G2A is a stress-inducible G protein-coupled receptor that is expressed on several cell types within atherosclerotic lesions. We demonstrated previously that G2A deficiency in mice increased aortic monocyte recruitment and increased monocyte:endothelial interactions. To investigate the impact of G2A deficiency in macrophages, we isolated peritoneal macrophages from G2A(+/+)ApoE(-/-) and G2A(-/-)ApoE(-/-) mice. G2A(-/-)ApoE(-/-) macrophages had significantly lower apoptosis than control macrophages. The prosurvival genes BCL-2, BCL-xL, and cFLIP were increased in G2A(-/-)ApoE(-/-) macrophages. Macrophages from G2A(-/-)ApoE(-/-) mice also had increased proinflammatory status that was indicative of a M1 macrophage phenotype. This was indicated by significantly increased nuclear translocation of nuclear factor kappaB, as well as production of interleukin-12p40, tumor necrosis factor alpha, and interleukin-6, and reduced expression of arginase-I. Moreover, G2A(-/-)ApoE(-/-) macrophages had reduced ability to engulf apoptotic cells in vitro. We examined atherosclerosis in mice fed a Western diet for 10 weeks and found that G2A deficiency increased lesion size in the aortic root by 50%. Plasma lipid levels were not changed in G2A(-/-)ApoE(-/-) mice. However, we found that absence of G2A increased the number of aortic macrophages and attenuated apoptosis in this cell type. Moreover, bone marrow transplantation studies indicated that deficiency of G2A in marrow-derived cells significantly contributed to atherosclerosis development. In the absence of G2A, increased macrophage activation and decreased apoptosis is associated with accumulation of macrophages in the aorta and increased atherosclerosis.
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PMID:G2A deficiency in mice promotes macrophage activation and atherosclerosis. 1910 13