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    Tissue plasminogen activator induces microglial inflammation via a noncatalytic molecular mechanism involving activation of mitogen-activated protein kinases and Akt signaling pathways and AnnexinA2 and Galectin-1 receptors

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    El pdf del art铆culo es la versi贸n pre-print.-- et al.Inflammatory responses mediated by glial cells play a critical role in many pathological situations related to neurodegeneration such as Alzheimer's disease. Tissue plasminogen activator (tPA) is a serine protease which best-known function is fibrinolysis, but it is also involved in many other physiological and pathological events as microglial activation. Here, we found that tPA is required for A脦虏-mediated microglial inflammatory response and tumor necrosis factor-脦卤 release. We further investigated the molecular mechanism responsible for tPA-mediated microglial activation. We found that tPA induces a catalytic-independent rapid and sustained activation of extracellular signal-regulated kinase (ERK)1/2, Jun N-terminal kinase (JNK), Akt, and p38 signaling pathways. Inhibition of ERK1/2 and JNK resulted in a strong inhibition of microglial activation, whereas Akt inhibition led to increased inflammatory response, suggesting specific functions for each signaling pathway in the regulation of microglial activation. Furthermore, we demonstrated that AnnexinA2 and Galectin-1 receptors are involved in tPA signaling and inflammatory response in glial cells. This study provides new evidences supporting that tPA plays a cytokine-like role in glial activation by triggering receptor-mediated intracellular signaling circuits and opens new therapeutic strategies for the treatment of neurological disorders in which neuroinflammation plays a pathogenic role. 漏 2011 Wiley Periodicals, Inc.Grant sponsor: Plan Nacional de I + D, Ministerio de Educaci贸n y Ciencia; Grant numbers: SAF2005-00704 (P.N.), SAF2008-04515 (A. P.) Fundaci贸 La Marat贸TV3; Grant number: 051110 (P.N.); PETRI-FEDER/Ministerio de Educaci贸n y Ciencia; Grant number: PET2006_0514 (P.N.); Grant sponsor: Instituto de Salud Carlos III-FEDER, Ministerio de Ciencia e Innovaci贸n; Grant numbers: PI080421 (P.N.), PI07/0455 (J.S.); Postdoctoral contract from the Ministerio de Ciencia e Innovaci贸n (Juan de la Cierva's Programme; D.P.).Peer Reviewe
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