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-1. However, it is not known whether IL-1 precursor is processed to mature IL-1 or released from VSMC, nor is it known whether either precursor or mature IL-1 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-1 constitutively at levels comparable to those produced after activation, and to determine which domains of IL-1 are important for its activity. Human VSMC were stably transfected with expression vectors directing constitutive expression of either full-length IL-1 precursor [IL-1-(1271)], its NH₂-terminal domain [IL-1-(1112)], or mature IL-1 [IL-1-(113271)]. Both IL-1-(1271) and IL-1-(113271) stable transfectants produced moderate levels of IL-1 (0.2-1.0 ng/10⁶ cells) and released low levels of IL-1 into the supernatant (<20 pg/ml). VSMC stably transfected with either IL-1-(1271) or IL-1-(113271) 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-1-(1271) was somewhat more effective than transfection with IL-1-(113271). Interestingly, VSMC transfected with IL-1-(113271) expression plasmids also expressed IL-1-(1271) mRNA, suggesting that IL-1-(113271) activates an IL-1-induced IL-1 autocrine loop. In contrast, neither proliferation rates nor morphology was affected by stable transfection with IL-1-(1112) expression plasmids. Exogenous IL-1 receptor antagonist partially reversed the enhanced DNA synthesis in VSMC transfected with either IL-1-(1271) or IL-1-(113271) expression plasmids, suggesting that the pro-proliferative effect of VSMC-derived IL-1 is at least partially mediated by signaling via the type I IL-1 receptor. These results demonstrate that IL-1 precursor is an autocrine growth factor for human VSMC and further indicate that amino acids 113-271 play a crucial role in its actions.

atherosclerosis; growth factors; interleukin-1 receptor antagonist

This article has been cited by other articles:

				K. Schultz, V. Murthy, J. B. Tatro, and D. Beasley Endogenous interleukin-1{alpha} promotes a proliferative and proinflammatory phenotype in human vascular smooth muscle cells Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2927 - H2934. [Abstract] [Full Text] [PDF]

				X. Yang, V. Murthy, K. Schultz, J. B. Tatro, K. A. Fitzgerald, and D. Beasley Toll-like receptor 3 signaling evokes a proinflammatory and proliferative phenotype in human vascular smooth muscle cells Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2334 - H2343. [Abstract] [Full Text] [PDF]

				X. Yang, D. Coriolan, V. Murthy, K. Schultz, D. T. Golenbock, and D. Beasley Proinflammatory phenotype of vascular smooth muscle cells: role of efficient Toll-like receptor 4 signaling Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1069 - H1076. [Abstract] [Full Text] [PDF]

				B. C. Berk Vascular Smooth Muscle Growth: Autocrine Growth Mechanisms Physiol Rev, July 1, 2001; 81(3): 999 - 1030. [Abstract] [Full Text] [PDF]

				S. Sasu, A. L. Cooper, and D. Beasley Juxtacrine effects of IL-1{alpha} precursor promote iNOS expression in vascular smooth muscle cells Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1615 - H1623. [Abstract] [Full Text] [PDF]

				J. G. Cannon Inflammatory Cytokines in Nonpathological States Physiology, December 1, 2000; 15(6): 298 - 303. [Abstract] [Full Text] [PDF]

				S. Sasu and D. Beasley Essential roles of Ikappa B kinases alpha and beta in serum- and IL-1-induced human VSMC proliferation Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1823 - H1831. [Abstract] [Full Text] [PDF]

				A. L. Cooper and D. Beasley Hypoxia stimulates proliferation and interleukin-1alpha production in human vascular smooth muscle cells Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1326 - H1337. [Abstract] [Full Text] [PDF]