Homeostatic role of interferons conferred by inhibition of IL-1-mediated inflammation and tissue destruction.
In addition to their well known immune and proinflammatory activities, IFNs possess homeostatic functions that limit inflammation and tissue destruction in a variety of conditions such as arthritis, osteolysis, and multiple sclerosis. The mechanisms underlying the homeostatic actions of IFNs are not well understood. We report here that both type I and type II IFNs (IFN-alpha, IFN-beta, and IFN-gamma, respectively) suppressed a broad range of proinflammatory and tissue-destructive activities of IL-1, including induction of inflammatory mediators, production of matrix metalloproteinases, macrophage tissue invasion, and cartilage degradation. IFN-alpha attenuated IL-1-mediated cell recruitment in vivo. IFNs completely suppressed the activation of IL-1 signal transduction pathways in macrophages. The mechanism of IFN-mediated inhibition of IL-1 action and signaling was modulation of IL-1R expression, which was also observed in vivo. IFN-gamma-mediated down-regulation of IL-1R type I expression was dependent on Stat1, a transcription factor typically considered to be a key mediator of macrophage activation by IFNs. These results identify cellular and molecular mechanisms that contribute to the homeostatic role of IFNs in limiting inflammation and associated tissue destruction.
Arthritis and Tissue Degeneration Program, Department of Medicine, Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University New York, NY 10021, USA.
Xiaoyu
X
Hu
Hao H
HH
Ho
Olivia
O
Lou
Chisa
C
Hidaka
Lionel B
LB
Ivashkiv
D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007372:Interferons / Q000502:physiology*; D007375:Interleukin-1 / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D007375:Interleukin-1; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma; D007372:Interferons; D020782:Matrix Metalloproteinases