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

By Fabiana S. Machado, Lísia Esper, Alexandra Dias, Rajat Madan, YuanYuan Gu, David Hildeman, Charles N. Serhan, Christopher L. Karp and Júlio Aliberti


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

Topics: Articles
Publisher: The Rockefeller University Press
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Provided by: PubMed Central

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  1. (2004). 15-epi-lipoxin A 4 – mediated induction of nitric oxide explains how aspirin inhibits acute infl ammation.
  2. (2002). All TRAFs are not created equal: common and distinct molecular mechanisms of TRAFmediated signal transduction.
  3. (1991). Arachidonic acid metabolism: role in infl ammation.
  4. (1995). Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions.
  5. (1996). Biochemical characterization and protein kinase C dependency of monokine-inducing activities of Toxoplasma gondii .
  6. (2000). Brief history of antipyretic therapy.
  7. by dendritic cells and their redistribution to T cell areas.
  8. (2000). CCR5 provides a signal for microbial induced production of IL-12 by CD8 alpha+ dendritic cells.
  9. (2004). Defective lipoxin-mediated anti-infl ammatory activity in the cystic fi brosis airway.
  10. (2006). Dendritic cell stimulation by mycobacterial
  11. (1999). Diff erential requirements for tumor necrosis factor receptor-associated factor family proteins in CD40-mediated induction of NF-kappaB and Jun N-terminal kinase activation.
  12. (2007). for proteasomal degradation and blocks Siglec 7-mediated responses.
  13. (2005). Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production.
  14. (2005). Host persistence: exploitation of anti-infl ammatory pathways by Toxoplasma gondii .
  15. (2000). Immunobiology of dendritic cells.
  16. (2006). Impact of lipoxin-mediated regulation on immune response to infectious disease.
  17. (1997). In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin
  18. (1994). Inhibition of NF-kappa B by sodium salicylate and aspirin.
  19. (1971). Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.
  20. (2007). Lipoxin A(4) levels in asthma: relation with disease severity and aspirin sensitivity.
  21. (2002). Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity.
  22. (2004). Lipoxins: potential antiinfl ammatory, proresolution, and antifi brotic mediators in renal disease.
  23. (2005). Mice defi cient in LRG-47 display enhanced susceptibility to Trypanosoma cruzi infection associated with defective hemopoiesis and intracellular control of parasite growth.
  24. (1985). Modes of action of aspirin-like drugs.
  25. (2003). Molecular mimicry of a CCR5 binding-domain in the microbial activation of dendritic cells.
  26. (1999). Paralysis of dendritic cell IL-12 production by microbial products prevents infection-induced immunopathology.
  27. (2002). Parasite-induced lipoxin A 4 is an endogenous regulator of IL-12 production and immunopathology in Toxoplasma gondii infection.
  28. (2001). PR-39 and PR-11 peptides inhibit ischemia-reperfusion injury by blocking proteasome-mediated I kappa B alpha degradation.
  29. (2003). Resolution of infl ammation: a new paradigm for the pathogenesis of periodontal diseases.
  30. (2007). Resolution of infl ammation: state of the art, defi nitions and terms.
  31. (2007). Resolution phase of infl ammation: novel endogenous anti-infl ammatory and proresolving lipid mediators
  32. (2007). SOCS proteins, cytokine signalling and immune regulation.
  33. (2006). Suppressor of cytokine signaling (SOCS) 2, a protein with multiple functions. Cytokine Growth Factor Rev.
  34. (1996). The interleukin 12 p40 gene promoter is primed by interferon in monocytic cells.
  35. (2002). The SOCS box: a tale of destruction and degradation.
  36. (1996). TRAF5, an activator of NF-kappaB and putative signal transducer for the lymphotoxin-beta receptor.
  37. (2004). TRAF6-dependent mitogen-activated protein kinase activation diff erentially regulates the production of interleukin-12 by macrophages in response to Toxoplasma gondii .
  38. (2004). TRAF7 potentiates MEKK3-induced AP1 and CHOP activation and induces apoptosis.
  39. (2001). Tumor necrosis factor receptor-associated factors (TRAFs).

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