Involvement of NF-κB Activation in Thrombin-Induced Human Vascular Smooth Muscle Cell Proliferation

Nakajima, Takeshi; Kitajima, Isao; Shin, Hiroshi; Takasaki, Ikuko; Shigeta, Koichiro; Abeyama, Kazuhiro; Yamashita, Yoshio; Tokioka, T; Soejima, Yasuko; Maruyama, Ikuro

doi:10.1006/bbrc.1994.2552

Cited by 77 publications

(55 citation statements)

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“…The BK receptor joins a growing number of G proteincoupled receptors that have been shown recently to activate NF-B upon agonist binding (40)(41)(42)(43). Our studies suggest that BK-induced IL-1␤ gene expression and NF-B activation are mediated by a receptor-coupled G protein system that involves the G i /G o class of G ␣ proteins.…”

Section: Discussionmentioning

confidence: 68%

Bradykinin stimulates NF-kappaB activation and interleukin 1beta gene expression in cultured human fibroblasts.

et al. 1996

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Section: Discussionmentioning

confidence: 68%

Bradykinin stimulates NF-kappaB activation and interleukin 1beta gene expression in cultured human fibroblasts.

et al. 1996

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“…Activated NF-B has been identified in our laboratory in cultured smooth muscle cells using electrophoretic mobility shift assays (Brand, K., unpublished observations). Additionally, two recent studies demonstrate NF-B activation in cultured smooth muscle cells by fibronectin (12) and thrombin (44).…”

Section: Discussionmentioning

confidence: 98%

Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion.

Brand¹,

Page²,

Rogler³

et al. 1996

J. Clin. Invest.

750

463

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“…36 Because IL-8 mRNA contains AU-rich sequences, p38 may interfere with thrombin-induced chemokine synthesis at a posttranscriptonal level. 37 Alternatively, thrombin is known to activate nuclear factor B (NF-B) in HUVECs, 38,39 and p38 may directly act at a transcriptional level through interaction with NF-B or AP-1 activation. Using this mechanism, p38 has been reported to be involved in TNF-␣-induced IL-6 mRNA synthesis in fibrosarcoma cells and, more recently, in lipopolysaccharide-induced TNF-␣ mRNA synthesis in neutrophils as well as in TNF-␣-induced MCP-1 mRNA synthesis in HUVECs.…”

Section: Discussionmentioning

confidence: 99%

The p38 mitogen-activated protein kinase pathway plays a critical role in thrombin-induced endothelial chemokine production and leukocyte recruitment

Marin

Farnarier

Grès

et al. 2001

Blood

100

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Thrombin, the terminal serine protease in the coagulation cascade, is a proinflammatory molecule in vivo and induces endothelial activation in vitro. The cellular signaling mechanisms involved in this function are unknown. The role of the p38 mitogen-activated protein kinase (MAPK) signaling pathway in thrombin-induced chemokine production was studied. Phosphorylation of both p38 MAPK and its substrate, ATF-2, was observed in human umbilical vein endothelial cells (HUVECs) stimulated with thrombin, with a maximum after 5 minutes of stimulation. Using the selective p38 MAPK inhibitor SB203580, there was a significant decrease in thrombin-induced interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) protein production and messenger RNA steady-state levels. In addition, SB203580 decreased IL-8 and MCP-1 production induced by the thrombin receptor-1 agonist peptide (TRAP), suggesting functional links between the thrombin G protein-coupled receptor and the p38 MAPK pathway. Furthermore, endothelial activation in the presence of SB203580 decreased the chemotactic activity of thrombin-stimulated HUVEC supernatant on neutrophils and monocytic cells. In contrast, the p42/p44 MAPK pathway did not appear to be involved in thrombin-or TRAP-induced endothelial chemokine production, because there was no reduction in the presence of the p42/ p44-specific inhibitor PD98059. These results demonstrate that the p38 rather than p42/44 MAPK signaling pathway plays an important role in thrombininduced endothelial proinflammatory activation and suggest that inhibition of p38 MAPK may be an interesting target for anti-inflammatory strategies in vascular diseases combining thrombosis and inflammation. IntroductionThrombin, a well-known procoagulant molecule, activates platelet aggregation and processing of fibrinogen into fibrin. 1 Three different thrombin receptors, belonging to the protease-activated receptor (PAR-1, -3, -4) family, have been identified on different cells. [2][3][4] PAR-2, another member of this family, does not seem to be activated by thrombin but, rather, by trypsin. 4 Following enzymatic cleavage of PAR-1, thrombin exhibits pleiotropic effects on cells. Notably, thrombin acts as a proliferation-inducing factor for smooth muscle cells and fibroblasts in vitro. 5 In addition, thrombin appears to be a potent proinflammatory molecule in vivo and in vitro. 6 Indeed, thrombin participates in the different steps of leukocyte-endothelium interactions by inducing in vitro endothelial expression of leukoendothelial adhesion molecules. Thrombin has been shown to induce P-selectin expression through a protein synthesis-independent mechanism and E-selectin as well as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression through gene transcription and protein synthesis. [7][8][9][10] Thus, thrombin may participate in the initial phase of rolling mediated by selectins, followed by firm leukoendothelial adhesion mediated by members of the immunoglobulin superfamily. 11 Thrombin also favors l...

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Involvement of NF-κB Activation in Thrombin-Induced Human Vascular Smooth Muscle Cell Proliferation

Cited by 77 publications

References 0 publications

Bradykinin stimulates NF-kappaB activation and interleukin 1beta gene expression in cultured human fibroblasts.

Bradykinin stimulates NF-kappaB activation and interleukin 1beta gene expression in cultured human fibroblasts.

Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion.

The p38 mitogen-activated protein kinase pathway plays a critical role in thrombin-induced endothelial chemokine production and leukocyte recruitment

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