Transforming growth factor-beta 1, but not dexamethasone, down-regulates nitric-oxide synthase mRNA after its induction by interleukin-1 beta in rat smooth muscle cells.

Nitric oxide (NO), which accounts for the biologic properties of endothelium-derived relaxing factor, is synthesized from L-arginine by nitric-oxide synthase (NOS). Two classes of NOS have been identified: a constitutive, calcium-dependent isozyme (cNOS) and an inducible, calcium-independent isozyme (iNOS). NO is generated after the induction of iNOS by cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha. As a potent vasodilator, NO may have an important role in the severe hypotension of septic shock. We investigated whether dexamethasone and transforming growth factor-beta 1 (TGF-beta 1) suppress iNOS mRNA after its induction by IL-1 beta. We found that IL-1 beta induced iNOS mRNA in rat aortic smooth muscle cells (RASMC) in a dose- and time-dependent fashion. IL-1 beta promoted a dramatic and prolonged induction of RASMC iNOS mRNA that peaked at 48 h. Dexamethasone prevented this induction of iNOS mRNA only when given before the addition of IL-1 beta. In contrast, TGF-beta 1 inhibited the induction of iNOS mRNA and NO production in RASMC both before and after the addition of IL-1 beta. After 24 h of IL-1 beta stimulation, TGF-beta 1 down-regulated the iNOS mRNA that had been induced during this initial time period. In nuclear run-on experiments, we found that the down-regulation of iNOS mRNA by TGF-beta 1 in RASMC occurred at the transcriptional level. Our observation that TGF-beta 1 mediates inhibition of RASMC iNOS mRNA after its induction by cytokines may be an important insight into the treatment of septic shock.