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Statins suppress interleukin‐6‐induced monocyte chemo‐attractant protein‐1 by inhibiting Janus kinase/signal transducers and activators of transcription pathways in human vascular endothelial cells
Author(s) -
Jougasaki Michihisa,
Ichiki Tomoko,
Takenoshita Yoko,
Setoguchi Manabu
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00612.x
Subject(s) - monocyte , stat1 , janus kinase , small interfering rna , farnesyl pyrophosphate , chemistry , stat3 , signal transduction , microbiology and biotechnology , transfection , biology , biochemistry , immunology , atp synthase , gene , enzyme
Background and purpose: The mechanisms of anti‐inflammatory actions of statins, 3‐hydroxy‐3‐methylglutaryl CoA (HMG‐CoA) reductase inhibitors, remain unclear. We investigated the effects of statins on interleukin (IL)‐6‐induced monocyte chemo‐attractant protein (MCP)‐1 expression and monocyte chemotaxis. Experimental approach: Cultures of human aortic endothelial cells (HAECs) were stimulated with IL‐6 in the absence and presence of statins. Gene expression and protein secretion of MCP‐1, phosphorylation of Janus kinase (JAK) and the signal transducers and activators of transcription (STAT) pathway, and human monocyte migration were examined. Key results: IL‐6 plus its soluble receptor sIL‐6R (IL‐6/sIL‐6R) promoted THP‐1 monocyte migration, and increased gene expression and protein secretion of MCP‐1, more than IL‐6 alone or sIL‐6R alone. Various statins inhibited IL‐6/sIL‐6R‐promoted monocyte migration and MCP‐1 expression in HAECs. Co‐incubation of mevalonate and geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, reversed the inhibitory effects of statins on MCP‐1 expression. Geranylgeranyl transferase inhibitor, but not farnesyl transferase inhibitor, suppressed IL‐6/sIL‐6R‐stimulated MCP‐1 expression. IL‐6/sIL‐6R rapidly phosphorylated JAK1, JAK2, TYK2, STAT1 and STAT3, which were inhibited by statins. Transfection of STAT3 small interfering RNA (siRNA), but not STAT1 siRNA, attenuated the ability of IL‐6/sIL‐6R to enhance THP‐1 monocyte migration. In addition, statins blocked IL‐6/sIL‐6R‐induced translocation of STAT3 to the nucleus. Conclusions and implications: Statins suppressed IL‐6/sIL‐6R‐induced monocyte chemotaxis and MCP‐1 expression in HAECs by inhibiting JAK/STAT signalling cascades, explaining why statins have anti‐inflammatory properties beyond cholesterol reduction.