Interleukin-10 inhibits postinjury tumor necrosis factor-mediated human vascular smooth muscle proliferation

Background. Both ischemic and direct vascular injury (angioplasty) result i n the elaboration of proinflammatory substances, including tumor necrosis f actor alpha (TNF), which may regulate vascular smooth muscle cell (VSMC) pr oliferation and promote vessel stenosis. Interleukin-10 (IL-10) is a pleiot ropic cytokine with potent antiinflammatory effects in many cells lines. We hypothesized that IL-10 could be used therapeutically to influence vascula r remodeling by inhibiting TNF-induced VSMC proliferation. The purposes of this study were (1) to determine whether human myocardium produces endogeno us TNF in response to ischemia-reperfusion, (2) to examine the effect of TN F on human arterial smooth muscle proliferation, and (3) to explore the pot ential therapeutic effect of IL-10 on unstimulated and TNF-stimulated VSMC proliferation. Materials and Methods. Right atrial muscle was ob tained from patients unde rgoing elective cardiac surgery. Atrial muscle was subjected to simulated i schemia and reperfusion in vitro and TNF was measured by immunoassay. Human aortic VSMCs were isolated and cultured. Proliferation assays were perform ed to determine the effect of TNF and IL-10 on VSMC growth. Results. Ischemia-reperfusion resulted in an increase in atrial myocellular TNF (94.5 +/- 15.8 pg/g wet tissue versus control 12.9 +/- 4.4 pg/g wet ti ssue, P < 0.002). Compared with control, TNF stimulated concentration-depen dent VSMC proliferation (P < 0.005). IL-10 alone did not influence VSMC gro wth. However, following TNF stimulation, IL-10 inhibited VSMC growth at a d ose as low as 0.1 pg/ml (P < 0.005). Conclusions. Ischemia-reperfusion insult results in increased endogenous my ocardial TNF accumulation. TNF stimulates VSMC growth which is abrogated by physiologically relevant levels of IL-10. This antiinflammatory cytokine m ay prove to be an effective therapeutic agent in regulating vessel wall rem odeling following both ischemic and direct cardiovascular injury (C) 1998 A cademic Press.