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Adiponectin Promotes Endotoxin Tolerance in Macrophages by Inducing IRAK-M Expression¹

Vassiliki Zacharioudaki^*,, Ariadne Androulidaki^*, Alicia Arranz^*, George Vrentzos, Andrew N. Margioris^2,* and Christos Tsatsanis^2,*

^* Department of Clinical Chemistry and Graduate Program on Molecular Basis of Human Disease, School of Medicine, University of Crete, Crete, Greece; and Department of Internal Medicine, University Hospital of Heraklion, Crete, Greece

High levels of plasma adiponectin are associated with low levels of inflammatory markers and cardioprotection. The mechanism via which adiponectin exerts its anti-inflammatory effect is yet unknown. In the present study, we demonstrate that globular adiponectin (gAd) induces the expression of the inactive isoform of IL-1R-associated kinases (IRAK), IRAK-M. Homologous deletion of IRAK-M in IRAK-M^–/– mice abolished the tolerogenic properties of gAd because pretreatment of IRAK-M^–/– macrophages with gAd did not suppress LPS-induced proinflammatory cytokine production. GAd activated the MAPKs MEK1/2 and ERK1/2 in macrophages via their upstream regulator Tpl2. Activation of ERK1/2 via Tpl2 appeared necessary for the induction of IRAK-M because gAd did not induce IRAK-M in Tpl2^–/– macrophages or in macrophages pretreated with the MEK1/2 inhibitor UO126. In addition, activation of PI3K and Akt1 also appeared necessary for the induction of IRAK-M by gAd, because treatment of Akt1^–/– macrophages or pretreatment of macrophages with the PI3K inhibitor wortmannin abolished gAd-induced IRAK-M expression. Analysis of IRAK-M expression in human peripheral blood cells confirmed that serum adiponectin was negatively associated with IRAK-M and responsiveness to LPS. In conclusion, our data demonstrate that IRAK-M is a major mediator of gAd-induced endotoxin tolerance in primary macrophages, expression of which depends on the activation of Tpl2/ERK and PI3K/Akt1 signaling pathways.

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 partly supported by the Hellenic Secretariat for Research and Technology (ENE 03E372; to A.N.M.) and by the Association for International Cancer Research (AICR07-0072; to C.T.).

² Address correspondence and reprint requests to Christos Tsatsanis, Department of Clinical Chemistry, School of Medicine, University of Crete, Heraklion GR-710 03, Crete, Greece; E-mail address: tsatsani{at}med.uoc.gr or Dr. Andrew N. Margioris, Department of Clinical Chemistry, School of Medicine, University of Crete, Heraklion GR-710 03, Crete, Greece; E-mail address: andym{at}med.uoc.gr

³ Abbreviations used in this paper: gAd, globular adiponectin; CRP, C-reactive protein; IRAK, IL-1R-associated kinase; IRAK-M, IL-1R-associated kinase M; TRAF, TNFR-associated factor; KC, keratinocyte-induced chemokine.