Interleukin-1β Inhibits Expression of p21(WAF1/CIP1) and p27(KIP1) and Enhances Proliferation in Response to Platelet-Derived Growth Factor-BB in Smooth Muscle Cells

Abstract

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)-1␤ 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-1␤ 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-1␤ enhances the proliferation induced by PDGF-BB independently of PDGF-A signaling. IL-1␤ 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-1␤ stimulates CDKs by downregulating p21 and p27. Consistent with this hypothesis is the finding that CDK2 activity, induced by PDGF-BB, is enhanced 2.3Ϯ0.2-fold in the presence of IL-1␤. Key Words: smooth muscle Ⅲ platelet-derived growth factor Ⅲ interleukin-1 Ⅲ p21(WAF1/CIP1) Ⅲ p27(KIP1) Conclusions-Our

The Cyclin-Dependent Kinase 2 Inhibitor Down-regulates Interleukin-1β-Mediated Induction of Cyclooxygenase-2 Expression in Human Lung Carcinoma Cells

“…1A, lane 2) after 8 hours. Enhancement of the activity of CDK2 by IL-1h has been reported before (19). We therefore explored the possibility that IL-1h-induced COX-2 expression may involve CDK2.…”

“…Induction of COX-2 expression by IL-1h operates at the transcriptional level involving transcription factors, such as nuclear factor-nB (NF-nB) and CCAAT/enhancer-binding protein (C/EBP), as well as at the level of mRNA stabilization in a extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent process (17,18). Interestingly, IL-1h also enhances the activity of the CDK2 (19). We therefore investigated whether IL-1h-induced COX-2 expression involves CDK2.…”

Role of the CDKN1A/p21, CDKN1C/p57, and CDKN2A/p16 Genes in the Risk of Atherosclerosis and Myocardial Infarction

“…2 In recent years, accumulating evidence has implicated various CKIs as important endogenous regulators of leukocyte and VSMCs proliferation in various pathophysiological situations. [3][4][5] The regulation of CKI expression/activity influences the response of VSMCs to mechanical stimuli (such as blood flow) and to molecules (such as nitric oxide, interleukines, angiotensin II and growth factors), and is mediated through the regulation of CKI expression/activity. [6][7][8][9][10] For example, reduced expression of p27 has been reported in primary atherosclerotic and restenotic tissue versus nondiseased arterial tissue.…”

Interleukin‐1 receptor antagonist (IL‐1ra) modulates endothelial cell proliferation

“…These EC data contrast with the role of IL-1 in VSMCs, where IL-1 enhances platelet-derived growth factor-BB (PDGF-BB) cell proliferation, an effect mediated by increased CDK2 activity [10]. Administration of IL1ra to these cells inhibits VSMC proliferation whilst IL-1ra in combination with PDGF-BB enhances proliferation [10].…”

“…Other studies have suggested a role for G1 cell cycle proteins in the IL-1 mediated proliferation of vascular smooth muscle cells [10] and the senescence of ECs [11]. Cyclin dependent kinase-2 (CDK2) activity is diminished in senescent HUVEC whilst bypassing senescence with telomerase restores CDK2 translation and activity [11].…”