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* Arthritis and Tissue Degeneration Program, Department of Medicine, Hospital for Special Surgery, New York, NY 10021; and
Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021
IL-27 is a member of the IL-12 family of cytokines that activates the Jak-STAT signaling pathway in a context-dependent manner and has pleiotropic effects on acquired immunity. IL-27 has the capacity to promote early stages of Th1 generation, but recent evidence has suggested a predominant suppressive effect on Th1, Th2, and Th17 differentiation. Although modest suppressive effects of IL-27 on myeloid lineage cells have been observed, there is limited knowledge about the role of IL-27 in the regulation of innate immunity. In this study we report that although in resting murine macrophages IL-27 had minimal if any effects, in resting human monocytes IL-27 had profound proinflammatory functions. IL-27 activated a STAT1-dominant pattern of signaling in human monocytes with the consequent activation of STAT1-dependent inflammatory target genes. IL-27 primed monocytes for augmented responses to TLR stimulation in a STAT1-dependent manner, altered IL-10 signaling, and attenuated IL-10-induced gene expression. Strikingly, IL-27 strongly suppressed TLR-induced IL-10 production in human monocytes. However, the proinflammatory effects of IL-27 on human monocytes were rapidly abrogated by LPS via a p38-mediated mechanism that inhibited IL-27 signaling. Our findings identify a predominantly proinflammatory function for IL-27 in human monocytes and suggest a mechanism by which the activating effects of IL-27 on innate immunity are attenuated as an immune response proceeds and IL-27 transitions to predominantly suppressive effects on acquired immunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by The Stavros S. Niarchos International Fellowship Exchange Program (to G.D.K.) and by a grant from the National Institutes of Health (to L.B.I.).
2 Address correspondence and reprint requests to Dr. Lionel B. Ivashkiv, Department of Medicine, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address: ivashkivl{at}hss.edu
3 Abbreviations used in this paper: M
, macrophage; BMDM, bone marrow-derived macrophage; CR1, complement receptor 1; DEPP, decidual protein-induced progesterone; h (prefix), human; IRF-1, IFN regulatory factor 1; m (prefix), murine; Pam3CysSer(Lys)4, (S)-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-Lys4-OH, 3HCl; PGDH, 15-hydroxy prostaglandin dehydrogenase; SHP-2, Src homology domain 2-containing phosphatase; shRNA, short hairpin RNA; SOCS, suppressor of cytokine signaling.
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