Transforming growth factor β1 and gamma interferon provide opposing signals to lipopolysaccharide-activated mouse macrophages

E. H.S. Hausmann, S. Y. Hao, J. L. Pace, M. J. Parmely

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Bacterial lipopolysaccharides (LPS) are potent inducers of macrophage activation, leading to the production of a number of proinflammatory mediators. Although several cytokines that prime macrophages for enhanced LPS-triggered responses have been identified, far less is known regarding the role that cytokines play in down-regulating macrophage responses to LPS. This study was designed to determine the effects of recombinant transforming growth factor β1 (rTGF-β1) on macrophage activation by LPS. Pretreatment of either mouse peritoneal macrophages or cells of the RAW 264.7 macrophage- like cell line with rTGF-β1 inhibited their ability to produce both tumor necrosis factor alpha (TNF-α) and nitric oxide (NO) in response to LPS. These inhibitory effects were reversed by increasing the concentration of LPS or by priming cells with optimal concentrations of recombinant gamma interferon (rIFN-γ). Pretreatment of cells with rTGF-β1 had only a modest inhibitory effect on the expression of TNF-α mRNA. By contrast, the expression of mRNA for the inducible form of nitric oxide synthase (iNOS), which is responsible for NO production in activated macrophages, was significantly inhibited by rTGF-β1 pretreatment. Thus, rTGF-β1-dependent suppression of macrophage TNF-α biosynthesis was manifest at a posttranscriptional level, whereas the inhibition of NO production correlated with a direct effect on iNOS gene expression. Importantly, both of these suppressive effects of rTGF-β1 were reversed by exposing the cells to priming concentrations of rIFN-γ. As with NO production, immunocytochemical analysis of iNOS expression in LPS-stimulated macrophages revealed that rIFN- γ and rTGF-β1 had antagonistic effects, with the former increasing, and the latter reducing, the number of iNOS-expressing cells induced by LPS. These data suggest that a balance between the priming effects of IFN-γ and the inhibitory effects of TGF-β1 can determine the overall level of macrophage activation induced by LPS.

Original languageEnglish (US)
Pages (from-to)3625-3632
Number of pages8
JournalInfection and Immunity
Volume62
Issue number9
StatePublished - 1994

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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