Constitutive expression of interleukin-1α precursor promotes human vascular smooth muscle cell proliferation

Author:

Beasley Debbie1,Cooper Angela L.1

Affiliation:

1. Division of Nephrology, Department of Medicine, and Tupper Research Institute, New England Medical Center Hospitals, Tufts University School of Medicine, Boston, Massachusetts 02111

Abstract

Vascular smooth muscle cell (VSMC) proliferation plays a critical role in the failure of vascular surgeries and contributes to the development of atherosclerotic lesions. Evidence that interleukin-1 (IL-1) is a mitogen for cultured VSMC has implicated its release by activated macrophages in the development of atherosclerosis. VSMC also produce IL-1, including the precursor form of IL-1α. However, it is not known whether IL-1α precursor is processed to mature IL-1α or released from VSMC, nor is it known whether either precursor or mature IL-1α functions as an autocrine growth factor. The goals of the present study were to establish whether proliferation is enhanced in human VSMC transfectants producing IL-1α constitutively at levels comparable to those produced after activation, and to determine which domains of IL-1α are important for its activity. Human VSMC were stably transfected with expression vectors directing constitutive expression of either full-length IL-1α precursor [IL-1α-(1—271)], its NH2-terminal domain [IL-1α-(1—112)], or mature IL-1α [IL-1α-(113—271)]. Both IL-1α-(1—271) and IL-1α-(113—271) stable transfectants produced moderate levels of IL-1α (0.2–1.0 ng/106cells) and released low levels of IL-1α into the supernatant (<20 pg/ml). VSMC stably transfected with either IL-1α-(1—271) or IL-1α-(113—271) expression plasmids proliferated rapidly compared with nontransfected or vector-transfected VSMC and displayed a distinct morphology characterized by elongated, spindle-shaped cells. Stable transfection with IL-1α-(1—271) was somewhat more effective than transfection with IL-1α-(113—271). Interestingly, VSMC transfected with IL-1α-(113—271) expression plasmids also expressed IL-1α-(1—271) mRNA, suggesting that IL-1α-(113—271) activates an IL-1-induced IL-1 autocrine loop. In contrast, neither proliferation rates nor morphology was affected by stable transfection with IL-1α-(1—112) expression plasmids. Exogenous IL-1 receptor antagonist partially reversed the enhanced DNA synthesis in VSMC transfected with either IL-1α-(1—271) or IL-1α-(113—271) expression plasmids, suggesting that the pro-proliferative effect of VSMC-derived IL-1α is at least partially mediated by signaling via the type I IL-1 receptor. These results demonstrate that IL-1α precursor is an autocrine growth factor for human VSMC and further indicate that amino acids 113–271 play a crucial role in its actions.

Publisher

American Physiological Society

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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