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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1293.)
© 2002 American Heart Association, Inc.

Vascular Biology

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; Jessie Deou; Bethany Walsh; Brenda Bourns; Alexander W. Clowes; Günter Daum

From the Department of Surgery, University of Washington, Seattle.

Correspondence to Günter Daum, PhD, Department of Surgery, Box 356410, University of Washington, 1959 NE Pacific St, Seattle, WA 98195-6410. 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 have been 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 • platelet-derived growth factor • interleukin-1 • p21(WAF1/CIP1) • p27(KIP1)

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