BLOCKING THE INTERLEUKIN-1 RECEPTOR INHIBITS LEUKOTRIENE-B4 AND PROSTAGLANDIN-E2 GENERATION IN HUMAN MONOCYTE CULTURES

Interleukin-1 is a potent stimulator of arachidonic acid (AA) metabolism and this activity could be attributed to the activation of the prostaglandin-forming enzyme cyclooxygenase or of the arachidonic-releasing enzyme phospholipase A2 or both. Prostaglandin E2 (PGE2), a cyclooxygenase product, and LTB4 (5-(S),12-(R)-dihydroxy-6,14-cis-8,10-(trans-eicosatetraenoic acid), a lipoxygenase product, are potent mediators of inflammation. Recently a new cytokine produced by macrophages and named interleukin-1 receptor antagonist (IL-Ira) (MW 22,000 Da) which specifically binds and blocks IL-1 receptors, has proven to be a potent inflammatory inhibitor. In our studies we found that monocyte suspensions, pretreated with hrIL-lra at increasing concentrations (0.25-250 ng/ml) for 10 min and then treated with LPS in an overnight incubation inhibits, in a dose-dependent manner, the generation of LTB4 as measured by the highly sensitive radioimmunoassay method. In monocytes pretreated with hrlL-lra (250 ng/ml) for 10 min and treated with arachidonic acid (10-5-10-9 M) and LPS overnight, the release of LTB4 was partially inhibited when compared to hrIL-1ra-untreated cells. Moreover, hrlL-lra (250 ng/ml) caused a partial inhibition of monocyte LTB4 production when the cells were activated with AA (10-7 M) and then treated with IL-1β (5 ng/ml) overnight or 24 hr incubation. In addition, human monocytes pretreated for 10 min with increasing doses of hrlL-lra (0.25-250 ng/ml) and then treated with hrIL-1α (5 ng/ml) orβ (5 ng/ml) for 18 hr, also resulted in the inhibition of PGE2 generation as measured by RIA when compared with hrIL-1ra-untreated cells. When the cells were treated with hrIL-1ra (250 ng/ml) and activated for 18 and 48 hr with increasing doses of hr IL-1β a strong inhibitory effect was found on PGE2 production. HrIL-1ra used at 15 ng/ml gave a partial inhibition of LTB4 generation, after LPS (1-100 ng/ml) treatment, while NDGA totally blocked the production of LTB4. Moreover, PGE2 released by macrophages activated with LPS (100 ng/ml) or hrIL-1β (5 ng/ml) at 18 hr incubation time was strongly inhibited when hrlL-lra (250 ng/ml) was used. These data suggest that the inhibition of LTB4 and PGE2 by this new macrophagederived monokine IL-1 ra occurs through the block of the IL-1 receptor, rather than phospholipase A2 and thus IL-1ra may offer apotential therapeutic approch to inflammatory states. © 1992.