ESAT-6 induced COX-2 expression involves coordinated interplay between PI3K and MAPK signaling

Kumar, Senthil A and Bansal, Kushagra and Holla, Sahana and Verma-Kumar, Shalu and Sharma, Pawan and Balaji, Kithiganahalli Narayanaswamy (2012) ESAT-6 induced COX-2 expression involves coordinated interplay between PI3K and MAPK signaling. In: Molecular Immunology, 49 (4). pp. 655-663.

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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-kappa B 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. (C) 2011 Elsevier Ltd. All rights reserved.

Item Type:	Journal Article
Publication:	Molecular Immunology
Publisher:	Elsevier Science
Additional Information:	Copyright of this article belongs to Elsevier Science.
Keywords:	Mycobacteria;ESAT-6;COX-2;TLR2;PI3K;MAPK
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	09 Mar 2012 10:23
Last Modified:	09 Mar 2012 10:23
URI:	http://eprints.iisc.ac.in/id/eprint/43858

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