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

Michihisa Jougasaki, Tomoko Ichiki, Yoko Takenoshita, Manabu Setoguchi

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1294-1303
Number of pages10
JournalBritish Journal of Pharmacology
Volume159
Issue number6
DOIs
StatePublished - Mar 2010

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Janus Kinase 1
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Transducers
Monocytes
Interleukin-6
Endothelial Cells
Proteins
Chemotaxis
Transferases
Small Interfering RNA
Anti-Inflammatory Agents
Janus Kinases
Hydroxymethylglutaryl CoA Reductases
Gene Expression
Aptitude

Keywords

  • Atherosclerosis
  • Cells
  • Endothelium
  • Inflammation
  • Interleukin-6
  • MCP-1, JAK
  • STAT
  • Statin

ASJC Scopus subject areas

  • Pharmacology

Cite this

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. / Jougasaki, Michihisa; Ichiki, Tomoko; Takenoshita, Yoko; Setoguchi, Manabu.

In: British Journal of Pharmacology, Vol. 159, No. 6, 03.2010, p. 1294-1303.

Research output: Contribution to journalArticle

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abstract = "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.",
keywords = "Atherosclerosis, Cells, Endothelium, Inflammation, Interleukin-6, MCP-1, JAK, STAT, Statin",
author = "Michihisa Jougasaki and Tomoko Ichiki and Yoko Takenoshita and Manabu Setoguchi",
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T1 - 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

AU - Jougasaki, Michihisa

AU - Ichiki, Tomoko

AU - Takenoshita, Yoko

AU - Setoguchi, Manabu

PY - 2010/3

Y1 - 2010/3

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Cells

KW - Endothelium

KW - Inflammation

KW - Interleukin-6

KW - MCP-1, JAK

KW - STAT

KW - Statin

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U2 - 10.1111/j.1476-5381.2009.00612.x

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