Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor β

Yoram Vodovotz, Christian Bogdan, John Paik, Qiao Wen Xie, Carl Nathan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

628 Scopus citations

Abstract

Activated mouse peritoneal macrophages produce nitric oxide (NO) via a nitric oxide synthase that is inducible by Interferon γ (IFN-γ): iNOS. We have studied the mechanisms by which transforming growth factor β1 (TGF-β) suppresses IFN-γ-stimulated NO production. TGF-β treatment reduced iNOS specific activity and iNOS protein in both cytosolic and particulate fractions as assessed by Western blot with monospecific anti-iNOS immunoglobuhn G. TGF-β reduced iNOS mRNA without affecting the transcription of iNOS by decreasing iNOS mRNA stability. Even after iNOS was already expressed, TGF-β reduced the amount of iNOS protein. This was due to reduction of iNOS mRNA translation and increased degradation of iNOS protein. The potency of TGF-β as a deactivator of NO production (50% inhibitory concentration, 5.6 ± 2 pM) may reflect its ability to suppress iNOS expression by three distinct mechanisms: decreased stability and translation of iNOS mRNA, and increased degradation of iNOS protein. This is the first evidence that iNOS is subject to other than transcriptional regulation.

Original languageEnglish
Pages (from-to)605-613
Number of pages9
JournalJournal of Experimental Medicine
Volume178
Issue number2
StatePublished - 1 Aug 1993
Externally publishedYes

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