REGULATION OF 12-LIPOXYGENASE BY CYTOKINES IN VASCULAR SMOOTH-MUSCLE CELLS

Increasing evidence suggests that cytokines such as interleukin-1 beta (IL-1), IL-4, and IL-8 may play an important role in the chronic infl ammation and cellular growth observed in cardiovascular diseases. The lipoxygenase (LO) pathway of arachidonate metabolism has also been rel ated to the pathology of hypertension and atherosclerosis. LO products have chemotactic, hypertrophic, and mitogenic effects in vascular cel ls, and the LO enzyme has been implicated in the oxidation of LDL. Fur thermore, earlier studies have shown that vascular smooth muscle cell (VSMC) growth factors such as angiotensin II and platelet-derived grow th factor can increase LO activity and expression in VSMCs. In the pre sent study, we have examined whether vasoactive and inflammatory cytok ines such as IL-1, IL-4, and IL-8 can modulate 12-LO activity and expr ession in porcine VSMCs and also whether they have growth-promoting ef fects in these cells. Treatment of porcine VSMCs with these cytokines led to significant increases in the levels of a cell-associated 12-LO product, 12-hydroxyeicosatetraenoic acid, as well as intracellular 12- LO enzyme activity. Furthermore, each of these cytokines led to a dose -dependent increase in 12-LO mRNA expression (333-base pair PCR produc t) as well as 12-LO protein expression (72 kD). In addition, all three interleukins could induce significant increases in VSMC DNA synthesis as well as proliferation. These results suggest that these cytokines have mitogenic effects in VSMCs and are also potent positive regulator s of the 12-LO pathway. Thus, enhanced 12-LO activity and expression m ay be a key mechanism for cytokine-induced VSMC migration and prolifer ation.