Role of IL-1β and COX2 in silica-induced IL-6 release and loss of pneumocytes in co-cultures

Abstract

The pro-inflammatory cytokines IL-1β, TNF-α and IL-6 are of great importance in the development of silica-induced lung damage and repair. In this study we investigated the role of IL-1β, TNF-α and COX2 in silica-induced regulation of IL-6 release and pneumocyte loss in various mono- and co-cultures of monocytes, pneumocytes and endothelial cells. All co-cultures with monocytes, and especially cultures including endothelial cells, showed an increase of silica-induced release of IL-6 compared to the respective monocultures. Treatment with the antagonist IL-1ra strongly decreased IL-1β and IL-6 release in contact co-cultures of monocytes and pneumocytes. COX2 up-regulation by silica and IL-1β was eliminated by IL-1ra. Inhibition of COX2 markedly reduced both IL-1β and IL-6 release. IL-1ra was more effective than COX2-inhibition in reduction of IL-6, but not of IL-1β. Silica-induced pneumocyte loss was reduced by IL-1β, but this effect was not counteracted by the IL-1 receptor antagonist. Our findings suggest that silica-induced IL-6 release from pneumocytes is mainly mediated via IL-1β release from the monocytes, via both COX2-dependent and -independent pathways. Notably, COX2-derived mediators seem crucial for a positive feed-back regulation of IL-1β release from the monocytes. In contrast to silica-induced IL-6, the reduction in pneumocyte loss by IL-1β does not seem to be regulated through an IL-1R1-dependent mechanism.