Cytokine-induced generation of multinucleated giant cells in vitro requires interferon-gamma and expression of LFA-1

Abstract

Multinucleated giant cells (MGC), which are a common feature of various pathologic states, were generated in vitro by cytokine-stimulation of human peripheral blood monocytes. As expected, conditioned medium, i.e. the supernatant of concanavalin A-stimulated peripheral blood mononuclear cells, readily caused generation of MGC. Addition of a monoclonal antibody (mAb) against interferon-gamma (IFN-gamma) completely abrogated this effect. IFN-gamma alone, however, had a much smaller effect than the conditioned medium. All other cytokines tested [including interleukin (IL)2, IL4 and tumor necrosis factor-alpha, which are known to activate monocytes] did not induce MGC nor did they enhance the effect of IFN-gamma. Formation of MGC could almost entirely be inhibited by mAb to the alpha or beta chain of LFA-1 and to a lesser extent by relatively high concentrations of a mAb against ICAM-1, one of the ligands of LFA-1. In contrast to the anti-IFN-gamma mAb that had no significant effect on the formation of monocyte clusters, mAb against LFA-1 inhibited clustering very efficiently. Antibodies directed to a number of different antigens present on the surface of monocytes (alpha chains of CR3 and CR4, HLA class I and II molecules, CD14 and CD16 antigens) had little or no effect on the generation of MGC. IFN-gamma, but not the concanavalin A-induced supernatant clearly enhanced expression of LFA-1 and ICAM-1 on monocytes. The results indicate that cytokine-induced generation of MGC is not possible without IFN-gamma, but most probably additional factor(s) enhance this effect. The mechanism(s) by which IFN-gamma promotes monocyte fusion apparently includes, among others, up-regulation of LFA-1 whose expression seems to be necessary but not sufficient for fusion.