STIMULATION OF HUMAN POLYMORPHONUCLEAR LEUKOCYTES BY RECOMBINANT HUMAN INTERLEUKIN-1-BETA

Leukocyte activation is a property of systemic infection. Animal experiments indicate interleukin-1 (IL-1) as a possible modulator, while contradictory results have been reported from in-vitro stimulation of isolated leukocytes. The purpose of the present study was to investigate the activation of isolated polymorphonuclear (PMN) leukocytes in vitro by preparations of recombinant human IL-1-beta and IL-1 receptor antagonist, which in earlier studies could elicit and abrogate, respectively, a sepsis-like syndrome in rabbits. They have also been shown to influence acute phase protein synthesis in mice and rats, and release of leukocyte cathepsin G in vivo. It was found that recombinant human IL-1-beta elicited a dose-dependent luminol-enhanced chemiluminescence response in isolated human PMN leukocytes in the dose range 8.8 x 10(-11) -8.8 x 10(-8)M. The effect could be blocked by prior treatment with the IL-1 receptor antagonist, indicating a direct effect on the specific IL-1 receptor. Preincubation by IL-1-beta enhanced the effect of a secondary challenge with phorbol 12-myristate 13-acetate or formyl-Met-Leu-Phe by 30-40%.The priming effect of rhIL-1-beta could also be blocked by the specific receptor antagonist. In this study incubation of PMN leukocytes with rhIL-1-beta failed to induce degranulation of both azurophil (neutrophil proteinase 4/proteinase 3) and specific (lactoferrin) granules. rhIL-1-beta has been shown to induce degranulation in vivo, which is thus indicated as an indirect effect. We conclude that IL-1-beta is a direct and specific, but probably weak stimulator of the PMN leukocyte. It may also be active as a "primer" of the leukocyte. The failure to reproduce the full picture of leukocyte activation seen in vivo does, however, indicate the action of secondary mediators in sepsis.