title: AMPKα1 deficiency amplifies proinflammatory myeloid APC activity and CD40 signaling.
abstract: AMPK is a serine/threonine kinase that regulates energy homeostasis and metabolic stress in eukaryotes. Previous work from our laboratory, as well as by others, has provided evidence that AMPKα1 acts as a negative regulator of TLR-induced inflammatory function. Herein, we demonstrate that AMPKα1-deficient macrophages and DCs exhibit heightened inflammatory function and an enhanced capacity for antigen presentation favoring the promotion of Th1 and Th17 responses. Macrophages and DCs generated from AMPKα1-deficient mice produced higher levels of proinflammatory cytokines and decreased production of the anti-inflammatory cytokine IL-10 in response to TLR and CD40 stimulation as compared with WT cells. In assays of antigen presentation, AMPKα1 deficiency in the myeloid APC and T cell populations contributed to enhanced IL-17 and IFN-γ production. Focusing on the CD154-CD40 interaction, we found that CD40 stimulation resulted in increased phosphorylation of ERK1/2, p38, and NF-κB p65 and decreased activation of the anti-inflammatory Akt -GSK3β-CREB pathway in DCs deficient for AMPKα1. Our data demonstrate that AMPKα1 serves to attenuate LPS and CD40-mediated proinflammatory activity of myeloid APCs and that AMPKα1 activity in both APC and T cells contributes to T cell functional polarization during antigen presentation.
authors.affiliation: 1.Louisville, KY 40292, USA. jill.suttles@louisville.edu.
authors.forename: Kelly Casey
authors.initials: KC
authors.lastname: Carroll
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Jill
authors.initials: J
authors.lastname: Suttles
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D020381:Interleukin-17; D008070:Lipopolysaccharides; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C440499:lipopolysaccharide, Escherichia coli O111 B4; C548179:Prkaa1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases
keywords: DC; Th1/Th2 cells; antigen processing/presentation; costimulation; inflammation; monocytes/macrophages