Modulation of rat vascular smooth muscle cell (VSMC) proliferation by cysteinyl leukotriene D4: a role for mediation of interleukin 1.

Recent studies suggest the involvement of inflammatory mechanisms in the progression of atherosclerosis. Cysteinyl leukotrienes and cytokines could orchestrate this progression by acting on the proliferation of vascular smooth muscle cells (VSMC). In cultures of rat VSMC, proliferation was modulated by cysteinyl leukotriene C4 (LTC4) and LTD4, but not LTE4. Co-culturing LTD4 with VSMC produced an increased cell proliferation as assessed by [3H]thymidine incorporation studies (200%) as well as cell counts (70%), using LTD4 at 10(-6)M compared to controls. LTD4 exerted its effect through an interleukin 1 (IL-1)-dependent autocrine regulatory mechanism. When IL-1 was inhibited by using a receptor antagonist (IL-1ra) and a polyclonal antibody to IL-1, we found an inhibition of VSMC proliferation. The increase of VSMC proliferation was associated with the autocrine production of interleukin-1 (IL-1) concomitant to LTD4 stimulation (55.5 +/- 2.5 pg/ml in controls and 177 +/- 0.5 pg/ml in 10(-6)M LTD4). These results may shed new light on the mechanism of inflammatory involvement during atherogenesis, suggesting that the control of cysteinyl leukotrienes may be important in inflammatory processes involving IL-1.