Adenosine 5'-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype.
Herein, we demonstrate a role of AMP-activated protein kinase (AMPK) as a potent counterregulator of inflammatory signaling pathways in macrophages. Stimulation of macrophages with anti-inflammatory cytokines (i.e., IL-10 and TGFbeta) resulted in the rapid phosphorylation/activation of AMPK, whereas stimulation of macrophages with a proinflammatory stimulus (LPS) resulted in AMPK dephosphorylation/inactivation. Inhibition of AMPKalpha expression by RNA interference dramatically increased the mRNA levels of LPS-induced TNF-alpha, IL-6, and cyclooxygenase-2. Likewise, expression of a dominant negative AMPKalpha1 in macrophages enhanced TNF-alpha and IL-6 protein synthesis in response to LPS stimulation, while diminishing the production of IL-10. In contrast, transfection of macrophages with a constitutively active form of AMPKalpha1 resulted in decreased LPS-induced TNF-alpha and IL-6 production, and heightened production of IL-10. In addition, we found that AMPK negatively regulated LPS-induced IkappaB-alpha degradation and positively regulated Akt activation, accompanied by inhibition of glycogen synthase kinase beta and activation of CREB. Thus, AMPK directs signaling pathways in macrophages in a manner that suppresses proinflammatory responses and promotes macrophage polarization to an anti-inflammatory functional phenotype.
Sag
Duygu
D
Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40292, USA.
Carling
David
D
Stout
Robert D
RD
Suttles
Jill
J
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D002460:Cell Line; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human