title: AMPK-dependent and independent effects of AICAR and compound C on T-cell responses.
abstract: As a master metabolic sensor, AMP-activated protein kinase (AMPK) is involved in different fundamental cellular processes. Regulation of AMPK activity either by agonists (e.g., AICAR) or by antagonists (e.g., Compound C) has been widely employed to study the physiological functions of AMPK. However, mounting evidence indicates AMPK-independent effects for these chemicals and how they regulate immune cell functions remains largely unknown. Herein, using T cells from AMPK conditional knockout mice and their wild type littermates, we demonstrate that AICAR and Compound C can, indeed, activate or inhibit AMPK activity in T cells, respectively. Specifically, AICAR inhibits, but Compound C promotes, Ca2+-induced T cell death in an AMPK-dependent manner. In contrast, our data also demonstrate that AICAR and Compound C inhibit T cell activation and cytokine production in an AMPK-independent manner. Moreover, we find that the AMPK-independent activity of AICAR and Compound Cis mediated via the mTOR signaling pathway in activated T cells. Our results not only reveal the critical role of AMPK in regulating T cell survival and function, but also demonstrate AMPK-dependent and independent rolesof AICAR/Compound C in regulating T cell responses, thus suggesting a context-dependent effect of these "AMPK regulators".
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: Enyu
authors.initials: E
authors.lastname: Rao
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Burn and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong, University, Jinan, Shandong, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: Jiaqing
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: Nejat K
authors.initials: NK
authors.lastname: Egilmez
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Suttles
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D005838:Genotype; D007155:Immunologic Factors / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D018345:Mice, Knockout; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012263:Ribonucleosides / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D020536:Enzyme Activators; D007155:Immunologic Factors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012263:Ribonucleosides; C516138:dorsomorphin; D000620:Aminoimidazole Carboxamide; C011651:acadesine; C546843:mTOR protein, mouse; C548179:Prkaa1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Immune response; Immunity; Immunology and Microbiology Section; T cell responses