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PMID: 7688028 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta.

The Journal of experimental medicine ·Vol. 178 ·No. 2 ·1993-08-01 ·Pages 605-13

Vodovotz Y, Bogdan C, Paik J, Xie QW, Nathan C

Abstract

Activated mouse peritoneal macrophages produce nitric oxide (NO) via a nitric oxide synthase that is inducible by interferon gamma (IFN-gamma): iNOS. We have studied the mechanisms by which transforming growth factor beta 1 (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 mRNA without affecting the transcription of iNOS by decreasing iNOS mRNA stability. Even after iNOS was already expressed, TGF-beta 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-beta 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.

MeSH Terms
Amino Acid Oxidoreductases/antagonists & inhibitors,biosynthesis,genetics Animals Cells, Cultured Enzyme Induction Female Interferon-gamma/pharmacology Macrophages/drug effects,metabolism Mice Nitric Oxide/metabolism Nitric Oxide Synthase RNA, Messenger/drug effects,metabolism Transcription, Genetic/drug effects Transforming Growth Factor beta/physiology
Chemicals
RNA, Messenger Transforming Growth Factor beta Nitric Oxide Interferon-gamma Nitric Oxide Synthase Amino Acid Oxidoreductases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Vodovotz Y
Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, New York 10021.
Bogdan C
Paik J
Xie Q W
Nathan C
References (42)
42 references, click to expand
  1. Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide.
    Proc Natl Acad Sci U S A. 1985 Nov;82(22):7738-42 PMID: 3906650
  2. Cytokine-activated endothelial cells express an isotype of nitric oxide synthase which is tetrahydrobiopterin-dependent, calmodulin-independent and inhibited by arginine analogs with a rank-order of potency characteristic of activated macrophages.
    Biochem Biophys Res Commun. 1991 Aug 15;178(3):823-9 PMID: 1714727
  3. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
    Anal Biochem. 1987 Apr;162(1):156-9 PMID: 2440339
  4. Cytosolic and membrane-bound nitric oxide synthase.
    Jpn J Pharmacol. 1991 Jun;56(2):217-20 PMID: 1715413
  5. Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein.
    Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7773-7 PMID: 1715579
  6. A possible novel pathway of regulation by murine T helper type-2 (Th2) cells of a Th1 cell activity via the modulation of the induction of nitric oxide synthase on macrophages.
    Eur J Immunol. 1991 Oct;21(10):2489-94 PMID: 1717284
  7. Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells.
    Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10480-4 PMID: 1720542
  8. Purification of the inducible murine macrophage nitric oxide synthase. Identification as a flavoprotein.
    J Biol Chem. 1991 Dec 5;266(34):22789-91 PMID: 1720773
  9. Induced RAW 264.7 macrophages express soluble and particulate nitric oxide synthase: inhibition by transforming growth factor-beta.
    Eur J Pharmacol. 1992 Feb 13;225(2):161-5 PMID: 1372563
  10. Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line.
    J Biol Chem. 1992 Mar 25;267(9):6370-4 PMID: 1372907
  11. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages.
    Science. 1992 Apr 10;256(5054):225-8 PMID: 1373522
  12. Stimulation of the nitric oxide synthase pathway in human hepatocytes by cytokines and endotoxin.
    J Exp Med. 1992 Jul 1;176(1):261-4 PMID: 1377225
  13. Induction and potential biological relevance of a Ca(2+)-independent nitric oxide synthase in the myocardium.
    Br J Pharmacol. 1992 Mar;105(3):575-80 PMID: 1378338
  14. Transforming growth factor-beta in leishmanial infection: a parasite escape mechanism.
    Science. 1992 Jul 24;257(5069):545-8 PMID: 1636092
  15. Induction of nitric oxide synthase in glial cells.
    J Neurochem. 1992 Sep;59(3):897-905 PMID: 1379633
  16. Cloned and expressed macrophage nitric oxide synthase contrasts with the brain enzyme.
    Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6711-5 PMID: 1379716
  17. Interleukin-8 inhibits the induction of nitric oxide synthase in rat peritoneal neutrophils.
    Biochem Biophys Res Commun. 1992 Jul 31;186(2):680-5 PMID: 1379804
  18. Nitric oxide as a secretory product of mammalian cells.
    FASEB J. 1992 Sep;6(12):3051-64 PMID: 1381691
  19. Epidermal growth factor suppresses nitric oxide and hydrogen peroxide production by keratinocytes. Potential role for nitric oxide in the regulation of wound healing.
    J Biol Chem. 1992 Oct 25;267(30):21277-80 PMID: 1383221
  20. The induction of nitric oxide synthase activity is inhibited by TGF-beta 1, PDGFAB and PDGFBB in vascular smooth muscle cells.
    Eur J Pharmacol. 1992 Jun 17;216(3):379-83 PMID: 1385162
  21. Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10.
    J Biol Chem. 1992 Nov 15;267(32):23301-8 PMID: 1429677
  22. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease.
    Nature. 1992 Oct 22;359(6397):693-9 PMID: 1436033
  23. Induction of calcium-independent nitric oxide synthase activity in primary rat glial cultures.
    Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10945-9 PMID: 1279698
  24. Negative regulation of hepatocyte growth factor gene expression in human lung fibroblasts and leukemic cells by transforming growth factor-beta 1 and glucocorticoids.
    J Biol Chem. 1992 Dec 15;267(35):24917-20 PMID: 1459995
  25. Tetrahydrobiopterin synthesis. An absolute requirement for cytokine-induced nitric oxide generation by vascular smooth muscle.
    J Biol Chem. 1992 Dec 25;267(36):25722-9 PMID: 1281471
  26. TGF beta suppresses casein synthesis in mouse mammary explants and may play a role in controlling milk levels during pregnancy.
    J Cell Biol. 1993 Jan;120(1):245-51 PMID: 8416990
  27. Biochemistry of nitric oxide and its redox-activated forms.
    Science. 1992 Dec 18;258(5090):1898-902 PMID: 1281928
  28. Inhibition of cytokine-induced nitric oxide production by transforming growth factor-beta 1 in human smooth muscle cells.
    J Physiol. 1992 Aug;454:451-65 PMID: 1282159
  29. Role of nitric oxide in antagonistic effects of transforming growth factor-beta and interleukin-1 beta on the beating rate of cultured cardiac myocytes.
    Mol Endocrinol. 1992 Nov;6(11):1921-30 PMID: 1282674
  30. Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia.
    Am J Physiol. 1992 Dec;263(6 Pt 2):H1963-6 PMID: 1481919
  31. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death.
    Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):770-4 PMID: 8421714
  32. Expression and secretion of type beta transforming growth factor by activated human macrophages.
    Proc Natl Acad Sci U S A. 1987 Sep;84(17):6020-4 PMID: 2888109
  33. The L-arginine dependent effector mechanism is induced in murine adenocarcinoma cells by culture supernatant from cytotoxic activated macrophages.
    J Leukoc Biol. 1988 Feb;43(2):187-92 PMID: 3422089
  34. Transforming growth factor-beta 1 modulates the expression of class II histocompatibility antigens on human cells.
    J Immunol. 1988 Jun 15;140(12):4217-23 PMID: 3131428
  35. Modulation of cytokine production by transforming growth factor-beta.
    J Immunol. 1989 Jun 15;142(12):4295-300 PMID: 2542408
  36. Hepatocytes produce nitrogen oxides from L-arginine in response to inflammatory products of Kupffer cells.
    J Exp Med. 1989 Nov 1;170(5):1769-74 PMID: 2509627
  37. Macrophage deactivating factor and transforming growth factors-beta 1 -beta 2 and -beta 3 inhibit induction of macrophage nitrogen oxide synthesis by IFN-gamma.
    J Immunol. 1990 Aug 1;145(3):940-4 PMID: 2115549
  38. Tumor necrosis factor alpha activates soluble guanylate cyclase in bovine glomerular mesangial cells via an L-arginine-dependent mechanism.
    J Exp Med. 1990 Dec 1;172(6):1843-52 PMID: 1979590
  39. Calmodulin-dependent endothelium-derived relaxing factor/nitric oxide synthase activity is present in the particulate and cytosolic fractions of bovine aortic endothelial cells.
    Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1788-92 PMID: 1705708
  40. Differential susceptibility of activated macrophage cytotoxic effector reactions to the suppressive effects of transforming growth factor-beta 1.
    J Immunol. 1991 Mar 15;146(6):1849-57 PMID: 1900875
  41. Transforming growth factor beta 2 inhibits interleukin 1 beta- and tumour necrosis factor alpha-induction of nitric oxide synthase in rat renal mesangial cells.
    Biochem Biophys Res Commun. 1991 Mar 15;175(2):372-9 PMID: 1708236
  42. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth.
    J Exp Med. 1986 May 1;163(5):1037-50 PMID: 2871125
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.178.2.605
Published
1993-08-01
Pages
605-13
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2191129
Subset
IM
Grants
NCI NIH HHS · CA-43610 · United States
External Links
PubMed source DOI: 10.1084/jem.178.2.605 PMC Full Text View journal details
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