FC-ALPHA RECEPTORS MEDIATE RELEASE OF TUMOR-NECROSIS-FACTOR-ALPHA ANDINTERLEUKIN-6 BY HUMAN MONOCYTES FOLLOWING RECEPTOR AGGREGATION

The functional capacity of the human monocyte receptor for the Fc port ion of IgA. (Fc alpha R) in mediating signal transduction was evaluate d by cytokine release. F(ab')(2) fragments of anti-Fc alpha R monoclon al antibodies (mAb) were used as specific probes to induce release of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Mul tivalent cross-linking by a secondary anti-mouse antibody [F(ab')(2) f ragments] induced a significant release of TNF-alpha and IL-6 by human blood mononuclear cells, indicating requirements for Fc alpha R aggre gation on the cell surface to transmit signals. Both cytokines were re leased exclusively by adherent cells, identifying monocytes as the res ponding cells within the mononuclear cell population. This cytokine re lease could not be due to contaminating endotoxins, because it was not abolished by polymyxin B, a lipopolysaccharide (LPS) inhibitor. Moreo ver, purified recombinant soluble Fc alpha R inhibited the anti-Fc alp ha R mAb-mediated cytokine release from blood monocytes, demonstrating that TNF-alpha and IL-6 were released in a receptor-specific manner. Our data suggest that Fc alpha R, through its capacity to mediate secr etion of IL-6, may play an important role in B-cell proliferation and immunoglobulin production. On the other hand, release of TNF-alpha fol lowing stimulation of Fc alpha R molecules directly implicates these r eceptors in amplification and regulation of the inflammatory process o ccurring during IgA-mediated host defence.