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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.
MedLine Citation:
PMID:  22162045     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 Aβ-mediated microglial inflammatory response and tumor necrosis factor-α 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. © 2011 Wiley Periodicals, Inc.
Authors:
David Pineda; Coral Ampurdanés; Manel G Medina; Joan Serratosa; Josep Maria Tusell; Josep Saura; Anna M Planas; Pilar Navarro
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-12-7
Journal Detail:
Title:  Glia     Volume:  -     ISSN:  1098-1136     ISO Abbreviation:  -     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8806785     Medline TA:  Glia     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011 Wiley-Liss, Inc.
Affiliation:
Cancer Research Programme, IMIM-Hospital del Mar, C/ Dr. Aiguader 88, 08003 Barcelona, Spain; Center for Genomic Regulation (CRG), C/ Dr. Aiguader 88, 08003 Barcelona, Spain.
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