title: Cot/tpl2 participates in the activation of macrophages by adiponectin.
abstract: Whereas the main function of APN is to enhance insulin activity, it is also involved in modulating the macrophage phenotype. Here, we demonstrate that at physiological concentrations, APN activates Erk1/2 via the IKKβ-p105/NF-κΒ1-Cot/tpl2 intracellular signal transduction cassette in macrophages. In peritoneal macrophages stimulated with APN, Cot/tpl2 influences the ability to phagocytose beads. However, Cot/tpl2 did not modulate the known capacity of APN to decrease lipid content in peritoneal macrophages in response to treatment with oxLDL or acLDL. A microarray analysis of gene-expression profiles in BMDMs exposed to APN revealed that APN modulated the expression of ∼3300 genes; the most significantly affected biological functions were the inflammatory and the infectious disease responses. qRT-PCR analysis of WT and Cot/tpl2 KO macrophages stimulated with APN for 0, 3, and 18 h revealed that Cot/tpl2 participated in the up-regulation of APN target inflammatory mediators included in the cytokine-cytokine receptor interaction pathway (KEGG ID 4060). In accordance with these data, macrophages stimulated with APN increased secretion of cytokines and chemokines, including IL-1β, IL-1α, TNF-α, IL-10, IL-12, IL-6, and CCL2. Moreover, Cot/tpl2 also played an important role in the production of these inflammatory mediators upon stimulation of macrophages with APN. It has been reported that different types of signals that stimulate TLRs, IL-1R, TNFR, FcγR, and proteinase-activated receptor-1 activate Cot/tpl2. Here, we demonstrate that APN is a new signal that activates the IKKβ-p105/NF-κΒ1-Cot/tpl2-MKK1/2-Erk1/2 axis in macrophages. Furthermore, this signaling cassette modulates the biological functions triggered by APN in macrophages.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain;
authors.forename: Carlos
authors.initials: C
authors.lastname: Sanz-Garcia
authors.affiliation: Pathobiology and Gastroenterology, Cleveland Clinic, Cleveland, Ohio, USA; and.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
authors.affiliation: Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, and Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lasunción
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain;
authors.forename: Margarita
authors.initials: M
authors.lastname: Fernandez
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; salemany@iib.uam.es.
authors.forename: Susana
authors.initials: S
authors.lastname: Alemany
mesh_terms: D052242:Adiponectin / Q000494:pharmacology*; D000818:Animals; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051550:I-kappa B Kinase / Q000502:physiology; D016753:Interleukin-10 / Q000502:physiology; D048369:MAP Kinase Kinase 1 / Q000502:physiology; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D008262:Macrophage Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D010587:Phagocytosis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000502:physiology*
chemical_list: D052242:Adiponectin; D018925:Chemokines; D016207:Cytokines; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D016753:Interleukin-10; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse; D048369:MAP Kinase Kinase 1
keywords: M1 polarization; MAP kinases; fat-derived hormone; foam cells; mircroarray; phagocytosis