INTERLEUKIN-1 INDUCES PROSTACYCLIN-DEPENDENT INCREASES IN CYCLIC-AMP PRODUCTION AND DOES NOT AFFECT CYCLIC-GMP PRODUCTION IN HUMAN VASCULAR SMOOTH-MUSCLE CELLS

Interleukin 1 (IL-1) is a pro-inflammatory cytokine which has direct vasorelaxant effects on vascular smooth muscle cells (VSMC). In the present study, IL-1 markedly increased intracellular levels of the vasodilatory mediator, cAMP, in human saphenous and human aortic VSMC. IL-1-induced cAMP was associated with a marked increase in prostacyclin (PGI(2)) production, and was reversed by indomethacin and tranylcypromine, inhibitors of cyclooxygenase acid PGI(2) synthetase respectively. Furthermore, PGI(2), but not PGE(2), was a potent inducer of cAMP production in HSVSMC, implicating a sole for PGI(2) in mediating IL-1-induced cAMP production. In previous studies, IL-1 increased immunoreactive cGMP production in human saphenous VSMC through a pathway inhibitable by soluble guanylate cyclase inhibitors, methylene blue and LY83583, but not by nitric oxide (NO) synthase inhibitors, suggesting a role of NO-independent activation of soluble guanylate cyclase. However, in the present study, it was found that cAMP cross-reacted significantly in cGMP radioimmunoassays employing three out of four commercial antisera, that IL-1 did not affect cGMP production in human saphenous or human aortic VSMC as determined by an RIA having low cAMP cross-reactivity, and that both LY83583 and methylene blue inhibited IL-1-induced increases in cAMP. The results implicate prostacyclin-dependent cAMP production as a mediator of the vasodilatory effects of IL-1 in humans. (C) 1995 Academic Press Limited.