The Journal of Experimental Medicine
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Published online April 14, 2008
doi:10.1084/jem.20072416
The Journal of Experimental Medicine, Vol. 205, No. 5, 1077-1086
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Machado et al.
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ARTICLE

 Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6

Fabiana S. Machado1, Lísia Esper1, Alexandra Dias1, Rajat Madan1, YuanYuan Gu1, David Hildeman2, Charles N. Serhan4, Christopher L. Karp1, and Júlio Aliberti1,3

1 Divisions of Molecular Immunology, 2 Immunobiology, and 3 Pulmonary Medicine, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229
4 Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115

CORRESPONDENCE Júlio Aliberti: julio.aliberti{at}cchmc.org OR Fabiana S. Machado: fabiana.machado{at}cchmc.org

Innate immune signaling is critical for the development of protective immunity. Such signaling is, perforce, tightly controlled. Lipoxins (LXs) are eicosanoid mediators that play key counterregulatory roles during infection. The molecular mechanisms underlying LX-mediated control of innate immune signaling are of interest. In this study, we show that LX and aspirin (ASA)-triggered LX (ATL) inhibit innate immune signaling by inducing suppressor of cytokine signaling (SOCS) 2–dependent ubiquitinylation and proteasome-mediated degradation of TNF receptor–associated factor (TRAF) 2 and TRAF6, which are adaptor molecules that couple TNF and interleukin-1 receptor/Toll-like receptor family members to intracellular signaling events. LX-mediated degradation of TRAF6 inhibits proinflammatory cytokine production by dendritic cells. This restraint of innate immune signaling can be ablated by inhibition of proteasome function. In vivo, this leads to dysregulated immune responses, accompanied by increased mortality during infection. Proteasomal degradation of TRAF6 is a central mechanism underlying LX-driven immune counterregulation, and a hitherto unappreciated mechanism of action of ASA. These findings suggest a new molecular target for drug development for diseases marked by dysregulated inflammatory responses.

Abbreviations used: ASA, aspirin; ATL, ASA-triggered lipoxin; JNK, c-Jun N-terminal kinase; LX, lipoxin; SOCS, suppressor of cytokine signaling; STAg, soluble Toxoplasma gondii tachyzoite antigen; TLR, Toll-like receptor; TRAF, TNF receptor–associated factor.

© 2008 Machado et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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