Abstract
Macrophages, as sentinels of robust host immunity, are key regulators of innate immune responses against invading mycobacteria; however, pathogenic mycobacteria survive in the infected host by subverting host innate immunity. Infection dependent expression of early secreted antigenic target protein 6 (ESAT-6) by Mycobacterium tuberculosis is strongly correlated with subversion of innate immune responses against invading mycobacteria. As a part of multifaceted immunity to mycobacterial infection, induced expression of cyclooxygenase-2 (COX-2) may act as an important influencing factor towards effective host immunity. In the current investigation, we demonstrate that ESAT-6 triggers COX-2 expression both in vitro and in vivo in a TLR2 dependent manner. Signaling perturbation data suggest that signaling dynamics of PI3K and p38 and JNK1/2 MAPK assume critical importance in ESAT-6 triggered expression of COX-2 in macrophages. Interestingly, ESAT-6 triggered PI3K-MAPK signaling axis holds the capacity to regulate coordinated activation of NF-κB and AP-1. Overall, current investigation provides mechanistic insights into ESAT-6 induced COX-2 expression and unravels TLR2 mediated interplay of PI3K and MAPK signaling axis as a rate-determining step during intricate host immune responses. These findings would serve as a paradigm to understand pathogenesis of mycobacterial infection and clearly pave a way towards development of novel therapeutics.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Bacterial / immunology
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Antigens, Bacterial / metabolism*
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Bacterial Proteins / immunology
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Bacterial Proteins / metabolism*
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Cell Line
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Cyclooxygenase 2 / biosynthesis*
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / immunology
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Cyclooxygenase 2 / metabolism
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Dinoprostone / immunology
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Dinoprostone / metabolism
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Immunity, Innate / genetics
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Immunity, Innate / immunology
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MAP Kinase Signaling System*
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinase 8 / immunology
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Mitogen-Activated Protein Kinase 8 / metabolism
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Mitogen-Activated Protein Kinase 9 / immunology
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Mitogen-Activated Protein Kinase 9 / metabolism
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Mycobacterium Infections / immunology
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Mycobacterium Infections / metabolism*
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Mycobacterium tuberculosis / immunology
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Mycobacterium tuberculosis / metabolism
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NF-kappa B / immunology
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NF-kappa B / metabolism
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Oncogene Protein v-akt / immunology
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Oncogene Protein v-akt / metabolism
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Phosphatidylinositol 3-Kinases / immunology
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Phosphatidylinositol 3-Kinases / metabolism*
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Toll-Like Receptor 2 / immunology
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Toll-Like Receptor 2 / metabolism
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Transcription Factor AP-1 / immunology
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Transcription Factor AP-1 / metabolism
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p38 Mitogen-Activated Protein Kinases / immunology
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Antigens, Bacterial
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Bacterial Proteins
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ESAT-6 protein, Mycobacterium tuberculosis
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NF-kappa B
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Tlr2 protein, mouse
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Toll-Like Receptor 2
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Transcription Factor AP-1
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Ptgs2 protein, mouse
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Cyclooxygenase 2
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Phosphatidylinositol 3-Kinases
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Mitogen-Activated Protein Kinase 9
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Oncogene Protein v-akt
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Mitogen-Activated Protein Kinase 8
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p38 Mitogen-Activated Protein Kinases
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Dinoprostone