Y. Vodovotz et al., MECHANISMS OF SUPPRESSION OF MACROPHAGE NITRIC-OXIDE RELEASE BY TRANSFORMING GROWTH-FACTOR-BETA, The Journal of experimental medicine, 178(2), 1993, pp. 605-613
Activated mouse peritoneal macrophages produce nitric oxide (NO) via a
nitric oxide synthase that is inducible by interferon gamma (IFN-gamm
a): iNOS. We have studied the mechanisms by which transforming growth
factor beta1 (TGF-beta) suppresses IFN-gamma-stimulated NO production.
TGF-beta treatment reduced iNOS specific activity and iNOS protein in
both cytosolic and particulate fractions as assessed by Western blot
with monospecific anti-iNOS immunoglobulin G. TGF-beta reduced iNOS mR
NA without affecting the transcription of iNOS by decreasing iNOS mRNA
stability. Even after iNOS was already expressed, TGF-beta reduced th
e amount of iNOS protein. This was due to reduction of iNOS mRNA trans
lation and increased degradation of iNOS protein. The potency of TGF-b
eta as a deactivator of NO production (50% inhibitory concentration, 5
.6 +/- 2 pM) may reflect its ability to suppress iNOS expression by th
ree distinct mechanisms: decreased stability and translation of iNOS m
RNA, and increased degradation of iNOS protein. This is the first evid
ence that iNOS is subject to other than transcriptional regulation.