PLATELET-DERIVED INTERLEUKIN-1 INDUCES CYTOKINE PRODUCTION, BUT NOT PROLIFERATION OF HUMAN VASCULAR SMOOTH-MUSCLE CELLS

During vascular injury, such as observed in atherosclerosis, restenosi s, vasculitides, transplantation, or sepsis, vascular smooth muscle ce lls (SMC) can be exposed to platelets or platelet products. Under thes e conditions proliferation or cytokine production of SMC stimulated by platelets or platelet products may contribute to regulation of vascul ar pathogenesis, Thus, we investigated interleukin-6 (IL-6) and IL-8 p roduction as well as proliferation of SMC in response to platelets or platelet lysates. Platelets not already preactivated by thrombin induc ed IL-6 (10- to 50-fold) or IL-8 production of unstimulated SMC in a c ell number dependent fashion. Preactivation of platelets with thrombin potently increased the platelet-mediated IL-6 (50- to 1,000-fold) and IL-8 production of SMC. Hirudin specifically inhibited the activation of platelets with thrombin, Isolated platelets cultured in the absenc e of SMC did not contain detectable IL-6 or IL-8. Prestimulation (4 ho urs) of SMC with pathophysiologically relevant substances (lipopolysac charide [LPS], tumor necrosis factor-alpha [TNF-alpha], or IL-1 alpha) further increased the platelet-induced cytokine production. The plate let-derived SMC stimulatory activity was IL-l, since IL-l receptor ant agonist (IL-1-Ra) inhibited the platelet-induced cytokine production o f SMC. Anti-platelet-derived growth factor (PDGF)antibody did not furt her reduce this activity, Thrombin itself stimulated expression of IL- 6 and IL-8 to some degree and induced IL-6 production of SMC synergist ically with IL-l, Platelets also induced proliferation of SMC, however , anti-PDGF antibodies, rather than IL-1-Ra blocked this response. The se data show that platelet-derived IL-l stimulates cytokine production of vascular smooth muscle cells, indicating that platelet-derived IL- l may contribute to regulation of local pathogenesis in the vessel wal l by activation of the cytokine regulatory network. (C) 1998 by The Am erican Society of Hematology.