COMPLEMENT C3 PRODUCTION IN HUMAN INTESTINAL EPITHELIAL-CELLS IS REGULATED BY INTERLEUKIN-1-BETA AND TUMOR-NECROSIS-FACTOR-ALPHA

Background: Sepsis and endotoxemia are associated with increased mucos al production of complement component C3; the enterocyte may be a sour ce of C3 in these conditions. Objective: To test the hypothesis that i nterleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alp ha) regulate the production of C3 in the enterocyte at the transcripti onal level and that this regulation is potentiated by interferon gamma (IFN-gamma). Methods: Cultured Caco-2 cells, a human intestinal epith elial cell line, were treated with various concentrations of human rec ombinant IL-1 beta (0.005-1.25 ng/mL) or TNF-alpha (1-1000 U/mL) with or without the addition of IFN-gamma (250 U/mL). C3 levels in the cult ure medium were measured by enzyme-linked immunosorbent assay and cell ular messenger RNA levels by Northern blot analysis. Results: Treatmen t of the Caco-2 cells with IL-1 beta or TNF-alpha resulted in a time-a nd dose-dependent increase in C3 production. The use of IFN-gamma alon e did not affect C3 production but potentiated the effect of IL-1 beta and TNF-alpha in a synergistic manner. C3 messenger RNA levels were i ncreased following stimulation with either cytokine. Conclusions: C3 p roduction in the enterocyte is regulated by IL-1 beta and TNF-alpha at the transcriptional level, and this response is potentiated by IFN-ga mma. The results suggest that C3 production in the intestinal mucosa m ay be regulated locally by cytokines in a paracrine or autocrine manne r.