REGULATION OF HUMAN ALVEOLAR MACROPHAGE-DERIVED AND BLOOD MONOCYTE-DERIVED INTERLEUKIN-8 BY PROSTAGLANDIN-E2 AND DEXAMETHASONE

Mononuclear phagocytes are important immune effector cells that play a fundamental role in cellular immunity. In addition to their antigen-presenting and phagocytic activities, monocytes/macrophages produce a vast array of regulatory and chemotactic cytokines. Interleukin-8 (IL-8), a potent neutrophil-activating and chemotactic peptide, is produced in large quantities by mononuclear phagocytes and may be an important mediator of local and systemic inflammatory events. In this investigation, we describe the effects of prostaglandin E2 (PGE2) and dexamethasone (Dex) on IL-8 mRNA and protein expression from lipopolysaccharide (LPS)-treated human peripheral blood monocytes (PBM) and alveolar macrophages (AM). We demonstrate the dose-dependent suppression of IL-8 from LPS-stimulated PBM by PGE2. Treatment of stimulated PBM with 10(-6) M PGE2 resulted in maximal inhibition, causing 60% suppression of both IL-8 mRNA and extracellular protein levels. In contrast, PGE2 (10(-6) to 10(-8) M) did not significantly alter IL-8 mRNA or protein expression from LPS-treated AM. Treatment of LPS-stimulated PBM and AM with Dex (10(-6) to 10(-8) M) resulted in 75% decline in IL-8 mRNA and extracellular protein from either cell population. Pretreatment of PBM with PGE, or Dex 1 or 2 h before LPS stimulation caused a significant suppression of steady-state IL-8 mRNA levels; however, administration of either of these modulators 1 or 2 h after LPS stimulation failed to have an inhibitory effect. In a similar fashion, pretreatment with Dex before LPS stimulation resulted in a significant decrease in AM-derived steady-state IL-8 mRNA levels, whereas no significant reduction in IL-8 mRNA was observed from AM treated with Dex 1 to 2 h after LPS stimulation. Our findings suggest that either PGE2 or corticosteroids may function as important immunomodulators of mononuclear phagocyte-derived IL-8. Furthermore. this regulation may be related to either the temporal activation or state of differentiation of the mononuclear phagocyte.