on May 23, 2002
Published online before print May 23, 2002, doi: 10.1161/01.ATV.0000023428.69244.49
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Submitted on April 19, 2002
Accepted on May 13, 2002
Interleukin-1ß Inhibits Expression of p21(WAF1/CIP1) and p27(KIP1) and Enhances Proliferation in Response to Platelet-Derived Growth Factor-BB in Smooth Muscle Cells
Tyler J. Nathe ;
From the Department of Surgery, University of Washington, Seattle.
* To whom correspondence should be addressed. E-mail: daum{at}u.washington.edu.
Objective—Intimal growth depends on smooth muscle cell (SMC) migration and proliferation and is regulated by thrombotic and inflammatory responses to vascular injury. Platelet-derived growth factor (PDGF)-BB and interleukin (IL)-1ß have been shown to contribute to intimal hyperplasia and lesion progression in atherosclerosis. Mitogenic effects of IL-1 on SMCs have been reported and are attributed to the expression of PDGF-A chain. In some, but not all, studies, IL-1ß was found to cooperate with growth factors, including PDGF, in stimulating proliferation. The molecular basis for such cooperative effects is unknown and is the subject of the present study.
Methods and Results—We demonstrate that in baboon aortic SMCs, IL-1ß enhances the proliferation induced by PDGF-BB independently of PDGF-A signaling. IL-1ß increases the phosphorylation of retinoblastoma protein, a pivotal step in the G1-to-S transition in the cell cycle. Analysis of expression levels of cyclins and cyclin-dependent kinase (CDK) inhibitors suggests that IL-1ß stimulates CDKs by downregulating p21 and p27. Consistent with this hypothesis is the finding that CDK2 activity, induced by PDGF-BB, is enhanced 2.3±0.2-fold in the presence of IL-1ß.
Conclusions—Our data suggest that IL-1ß may promote SMC proliferation after vascular injury and in atherogenesis by suppression of PDGF-BB--induced p21 and p27.
Key words: smooth muscle • plate-derived growth factor • interleukin-1 • p21(WAF1/CIP1) • p27(KIP1)
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