TRANSFORMING GROWTH-FACTOR-BETA INHIBITS INTERFERON-GAMMA-INDUCED HLA-DR EXPRESSION BY CULTURED HUMAN FIBROBLASTS

This study shows the induction of HLA-DR (DR) in fibroblasts by IFN-ga mma and investigates the molecular mechanisms involved in the further DR down-regulation by TGF-beta 1. Kinetics of DR induction on human de rmal fibroblasts by IFN-gamma showed that 1 hr of exposure was require d to induce detectable levels of DR, and maximal DR expression was ach ieved only after 2 days of exposure to IFN-gamma. TGF-beta 1 inhibited DR induction by IFN-gamma, although complete inhibition never could b e achieved, even with high concentrations of TGF-beta 1 and low concen trations of IFN-gamma. Inhibition was not accounted for by reduction i n cell numbers, as TGF-beta 1 stimulated growth of the fibroblasts. In hibition of DR induction was seen only if TGF-beta 1 was added during the first 24 hr of IFN-gamma treatment. TGF-beta 1 inhibited equally w ell if the cells were pretreated for as little as 1 hr and then washed before addition of IFN-gamma. TGF-beta 1 did not cause an overall sup pression of protein synthesis. Northern blot analysis revealed that TG F-beta 1 greatly reduced the steady-state level of DR beta mRNA induce d by IFN-gamma at 24 hr, and then DRP transcripts became undetectable at later stages. It is concluded that early intracellular signals must build up to stimulate maximum DR synthesis, which, later on, are inac tivated or degraded by the action of TGF-beta 1. We suggest that these mechanisms regulating DR gene transcription involve the action of gen es coding for specific IFN-gamma-inducible transcriptional factors tha t are turned on and off in an expeditious manner. Copyright (C) 1996 E lsevier Science Ltd