Adiponectin promotes endotoxin tolerance in macrophages by inducing IRAK-M expression.
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.
Department of Clinical Chemistry, Graduate Program on Molecular Basis of Human Disease, School of Medicine, University of Crete, Crete, Greece.
Vassiliki
V
Zacharioudaki
Ariadne
A
Androulidaki
Alicia
A
Arranz
George
G
Vrentzos
Andrew N
AN
Margioris
Christos
C
Tsatsanis
D052242:Adiponectin / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D004731:Endotoxins / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D053592:Interleukin-1 Receptor-Associated Kinases / Q000096:biosynthesis* / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology
D052242:Adiponectin; D004731:Endotoxins; D019869:Phosphatidylinositol 3-Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases