LYMPHOCYTES PRODUCE IL-1-BETA IN RESPONSE TO FC-GAMMA RECEPTOR CROSS-LINKING - EFFECTS ON PARENCHYMAL-CELL IL-8 RELEASE

Neutrophils mediate tissue injury in response to immune complexes, alt hough the factors that induce their recruitment are incompletely under stood, We have reported that lymphocytes mag be important regulators o f monocyte and macrophage IL-8 release in the presence of immobilized IgG, Since tissue parenchymal cells are important local producers of I L-8 but are not directly stimulated by Fc gamma R cross-linking, we hy pothesized that lymphocytes may also regulate parenchymal IL-8 release , Supernatants from lymphocytes incubated on immobilized IgG induced p rimary human fibroblasts and human mesangial cells to produce IL-8 (17 +/- 3.5 and 44 +/- 8 ng/ml, respectively). Fibroblast and mesangial c ell IL-8 mRNA levels were similarly increased by the conditioned lymph ocyte supernatant, Immobilized anti-human Fc gamma RIII but not Fc gam ma RI or Fc gamma RII Abs, could stimulate this IL-8-inducing activity in lymphocytes, suggesting that Fc gamma RIII-bearing lymphocytes wer e responsible, Supernatants from lymphocytes incubated on immobilized IgG contained 2.2 +/- 0.8 ng/ml of IL-1 beta, while enriched monocyte preparations from the same donors incubated on immobilized IgG release d only 0.1 +/- 0.04 ng/ml of IL-1 beta (p = 0.05), Consistent with the identification of IL-1 beta as the lymphocyte factor, fibroblast or m esangial cell IL-8 release induced by the IgG-stimulated lymphocyte su pernatants was inhibited by 1) the combination of IL-1R antagonist and soluble type II IL-1R, 2) an IL-1-converting enzyme inhibitor, or 3) anti-IL-1 beta but not preimmune Abs. These data suggest that targeted deposits of IgG can stimulate Fc gamma RIII-bearing lymphocytes to pr oduce IL-1 beta, which induces parenchymal cell IL-8 release.