MODULATION OF PROINFLAMMATORY CYTOKINE RELEASE FROM HUMAN POLYMORPHONUCLEAR LEUKOCYTES BY GAMMA-INTERFERON

Polymorphonuclear leukocytes (PMN) have been identified as important s ources of various proinflammatory cytokines. Since Interferon-gamma (I FN-gamma) is one of the activating factors of PMN, we have examined it s effect on PMN-derived cytokine production. Recently, we demonstrated that IFN-gamma inhibits the release of IL-8 by PMN stimulated for 2 h r with different agonists. In this report, we show that the IFN-gamma- dependent inhibition of IL-8 release by PMN stimulated with lipopolysa ccharide (LPS), tumor necrosis factor (TNF), and/or interleukin-1 beta (IL-1 beta), but not with Y-IgG, is a transient phenomenon. Indeed, P MN stimulated in the presence of IFN-gamma for 18 hr demonstrated an e nhanced expression of IL-8 antigen in cell-free supernatants compared with stimuli alone. This enhanced accumulation of IL-8 partially refle cted changes at the level of cell-associated versus cell-secreted IL-8 as PMN incubated with IFN-gamma secreted significantly more IL-8, rel ative to untreated cells. Unlike IL-8, the LPS-stimulated production o f TNF and IL-1 beta, as well as the TNF-stimulated production of IL-1 beta, was markedly enhanced by IFN-gamma over the entire incubation pe riod (up to 18 hr). Addition of anti-TNF and anti-IL-1 beta antibodies to IFN-gamma plus LPS-treated PMN indicated that the LPS-induced prod uction of endogenous TNF and IL-1 beta, which was further potentiated by IFN-gamma pretreatment, mediated in autocrine fashion the enhanced LPS-induced IL-8 accumulation observed at 18 hr. Furthermore, as shown by Northern blot analysis, all the effects of IFN-gamma on LPS-stimul ated PMN were paralleled by changes at the level of TNF, IL-1 beta, an d IL-8 mRNA expression. Taken together, these findings identify novel biological actions of IFN-alpha as a modulator of the acute inflammato ry response. (C) 1994 Academic Press, Inc.