Modulation of C5a-mediated effector functions of human polymorphonuclear leukocytes by tumor necrosis factor alpha and granulocyte macrophage colony-stimulating factor

At the site of acute inflammation, leukocytes are confronted with multiple mediators which are expected to modulate each other with respect to cell re sponses to the individual ligand. In the present study, we compared the eff ects of the classical chemoattractants FMLP, PAF and LTB4, of the chemokine IL-8 and of TNF alpha, GM-CSF, IFN-gamma and IL-1 beta on C5a-induced chem otaxis, degranulation, oxidative burst and expression of adhesion molecules of human neutrophils in vitro. Upon preincubation, TNF alpha as well as GM -CSF dose-dependently inhibited C5a-mediated chemotaxis, but augmented the release of elastase as well as respiratory burst activity. The effects of t he two cytokines were accompanied by a downregulation of C5a receptors as d etermined by Scatchard analysis using I-125-labeled C5a. Compared on a mola r basis, TNF alpha was more effective than GM-CSF. C5a-induced expression o f beta(2)-integrins was only moderately influenced by TNF alpha and GM-CSF. C5a itself diminished chemotaxis as well as degranulation and oxidative bu rst in response to a second dose of the same ligand (homologous desensitiza tion), whereas heterologous desensitization by FMLP and IL-8 was restricted to C5a-induced degranulation or not observed (PAF, LTB4). The cytokine eff ects are likely to be a consequence of altered C5a receptor expression as w ell as of postreceptor events. In concert with C5a, certain cytokines may s hift neutrophil effector functions from migration to exocytosis, an essenti al step within the sequence of events in a coordinated inflammatory respons e. Copyright (C) 1999 S. Karger AG, Basel.