Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10.
Transforming growth factor (TGF)-beta and interleukin (IL)-10 inhibited lipopolysaccharide (LPS)-induced macrophage production of the inflammatory cytokines tumor necrosis factor-alpha (TNF), IL-1 alpha, and IL-1 beta by contrasting post-transcriptional mechanisms. TGF-beta acted slowly and late, as it required 12-16 h to exert a suppressive effect, and inhibited TNF production even when added 6 h after LPS. TGF-beta affected neither the level of TNF mRNA, the release of preformed TNF nor the degradation of TNF. Thus, TGF-beta appeared to inhibit translation of TNF mRNA. IL-10 not only suppressed TNF release to a 25-fold greater extent than TGF-beta, but also inhibited release of IL-1. In contrast to TGF-beta, IL-10 acted on an early step in cytokine production, its effect being maximal 3 h after addition of LPS. Unlike TGF-beta, IL-10 markedly suppressed TNF, IL-1 alpha, and IL-1 beta mRNA levels. However, this was accomplished without suppressing transcription of the corresponding genes. Moreover, cycloheximide antagonized the IL-10-dependent reduction in cytokine mRNA levels. Thus, IL-10 may induce a ribonuclease active on cytokine transcripts or may induce a protein that enhances the susceptibility of TNF, IL-1 alpha, and IL-1 beta mRNAs to ribonucleolytic action. We conclude that IL-10 and TGF-beta induce different phenotypes of macrophage deactivation, and deactivate macrophages by different mechanisms: IL-10 promotes degradation of cytokine mRNA, while TGF-beta primarily suppresses translation.
Bogdan
C
C
Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, New York 10021.
Paik
J
J
Vodovotz
Y
Y
Nathan
C
C
D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000378:metabolism; D016753:Interleukin-10 / Q000494:pharmacology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D013755:Tetradecanoylphorbol Acetate