IFN-GAMMA INHIBITS THE PRODUCTION OF LATENT TRANSFORMING GROWTH-FACTOR-BETA-1 BY MOUSE INFLAMMATORY MACROPHAGES

Transforming growth factor (TGF)-beta is a multifunctional cytokine, w hich in mammals exists in three isoforms (TGF-beta 1, 2 and 3). It is synthesized by a variety of cells including macrophages, and exerts po tent immunoregulatory effects such as the inhibition of Th1 developmen t and the suppression or reversal of IFN-gamma-induced macrophage acti vation. In this study we analyzed the effect of IFN-gamma on the produ ction of TGF-beta 1 by thioglycolate-elicited mouse peritoneal macroph ages under serum-free conditions. Untreated macrophages released TGF-b eta 1 in its latent form, which became detectable in a capture ELISA s pecific for active TGF-beta 1 after acid activation of the culture sup ernatants. Treatment with IFN-gamma reduced the amount of latent TGF-b eta 1 in the culture supernatants in a dose-dependent fashion. The eff ect of IFN-gamma was confirmed by a newly developed Western blot syste m for the detection of mouse TGF-beta 1 protein, IFN-gamma only weakly (16-24%) reduced the levels TGF-beta 1 mRNA at early and late time po ints of stimulation, and no evidence was obtained that IFN-gamma suppr esses the secretion of latent TGF-beta 1. Thus, inhibition of TGF-beta 1 production by IFN-gamma is most likely due to decreased synthesis a nd/or stability of the TGF-beta 1 protein, and might be important for the generation of fully activated macrophages and a Th1 response.