DIFFERENTIAL REGULATION OF CYCLOOXYGENASE-1 AND CYCLOOXYGENASE-2 BY INTERLEUKIN-1-BETA, TUMOR-NECROSIS-FACTOR-ALPHA, AND TRANSFORMING GROWTH-FACTOR-BETA-1 IN HUMAN LUNG FIBROBLASTS

In the present studies we found that incubation of human lung fibrobla sts with transforming growth factor-beta 1 (TGF-beta 1) potentiated th e interleukin-1 beta (IL-1 beta) and/or tumor necrosis factor-alpha (T NF-alpha)-stimulated production of prostaglandin E-2 (PGE(2)). Analysi s of fibroblast proteins showed the induction of cyclooxygenase-1 (Cox -1) by TGF-beta 1 and the induction of Cox-2 by IL-1 beta and TNF-alph a. The levels of transcripts for Cox-1 were minimally modified by IL-1 beta or TNF-alpha, however, they were increased by 12-fold by TGF-bet a 1. Transcripts for Cox-2 were induced by IL-1 beta or TNF-alpha and their induction was potentiated by TGF-beta 1. TGF-beta 1 alone did no t induce Cox-2 transcripts. In vitro transcription assays showed that IL-1 beta and TNF-alpha increased the transcription of the Cox-a gene, whereas TGF-beta 1 had no effect. Additions of TGF-beta did not incre ase further the transcription of Cox-2 in IL-1 beta-treated cells, but increased the stability of the corresponding transcripts. The transcr iption rate of the Cox-1 gene was not increased by any of the cytokine s studied. In summary, we demonstrate that the potentiation of PGE, pr oduction by TGF-beta 1 in IL-1 beta and TNF-alpha-treated fibroblasts is the result of transcriptional stimulation of the Cox-2 gene by IL-1 beta and TNF-alpha and the stabilization of the resulting transcripts by TGF-beta 1 (C) 1998 Academic Press.