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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 IKK?-p105/NF-??1-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-1?, IL-1?, TNF-?, 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, Fc?R, and proteinase-activated receptor-1 activate Cot/tpl2. Here, we demonstrate that APN is a new signal that activates the IKK?-p105/NF-??1-Cot/tpl2-MKK1/2-Erk1/2 axis in macrophages. Furthermore, this signaling cassette modulates the biological functions triggered by APN in macrophages.

SUBMITTER: Sanz-Garcia C

PROVIDER: S-EPMC4021433 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Cot/tpl2 participates in the activation of macrophages by adiponectin.

Sanz-Garcia Carlos C Nagy Laura E LE Lasunción Miguel A MA Fernandez Margarita M Alemany Susana S

Journal of leukocyte biology 20140214 6

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 ...[more]

PMID: 24532642

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Project description:BackgroundMicroglia and macrophages (MG/M?) have a diverse range of functions depending on unique cytokine stimuli, and contribute to neural cell death, repair, and remodeling during central nervous system diseases. While IL-1 has been shown to exacerbate inflammation, it has also been recognized to enhance neuroregeneration. We determined the activating phenotype of MG/M? and the impact of IL-1 in an in vivo spinal cord injury (SCI) model of IL-1 knock-out (KO) mice. Moreover, we demonstrated the contribution of IL-1 to both the classical and alternative activation of MG in vitro using an adult MG primary culture.MethodsSCI was induced by transection of the spinal cord between the T9 and T10 vertebra in wild-type and IL-1 KO mice. Locomotor activity was monitored and lesion size was determined for 14 days. TNF? and Ym1 levels were monitored to determine the MG/M? activating phenotype. Primary cultures of MG were produced from adult mice, and were exposed to IFN? or IL-4 with and without IL-1?. Moreover, cultures were exposed to IL-4 and/or IL-13 in the presence and absence of IL-1?.ResultsThe locomotor activity and lesion area of IL-1 KO mice improved significantly after SCI compared with wild-type mice. TNF? production was significantly suppressed in IL-1 KO mice. Also, Ym1, an alternative activating MG/M? marker, did not increase in IL-1 KO mice, suggesting that IL-1 contributes to both the classical and alternative activation of MG/M?. We treated primary MG cultures with IFN? or IL-4 in the presence and absence of IL-1?. Increased nitric oxide and TNF? was present in the culture media and increased inducible NO synthase was detected in cell suspensions following co-treatment with IFN? and IL-1?. Expression of the alternative activation markers Ym1 and arginase-1 was increased after exposure to IL-4 and further increased after co-treatment with IL-4 and IL-1?. The phenotype was not observed after exposure of cells to IL-13.ConclusionsWe demonstrate here in in vivo experiments that IL-1 suppressed SCI in a process mediated by the reduction of inflammatory responses. Moreover, we suggest that IL-1 participates in both the classical and alternative activation of MG in in vivo and in vitro systems.

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Cot/tpl2 participates in the activation of macrophages by adiponectin.

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Cot/tpl2 participates in the activation of macrophages by adiponectin.

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