Interleukin-1beta inhibits expression of p21(WAF1/CIP1) and p27(KIP1) and enhances proliferation in response to platelet-derived growth factor-BB in smooth muscle cells.

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)-1beta 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-1beta 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-1beta enhances the proliferation induced by PDGF-BB independently of PDGF-A signaling. IL-1beta increases the phosphorylation of retinoblastoma protein, a pivotal step in the G(1)-to-S transition in the cell cycle. Analysis of expression levels of cyclins and cyclin-dependent kinase (CDK) inhibitors suggests that IL-1beta 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-1beta.
CONCLUSIONS: Our data suggest that IL-1beta may promote SMC proliferation after vascular injury and in atherogenesis by suppression of PDGF-BB-induced p21 and p27.