HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 18, 12501-12511, May 2, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/18/12501    most recent M709960200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Narayana, Y. Articles by Balaji, K. N. PubMed PubMed Citation Articles by Narayana, Y. Articles by Balaji, K. N.

NOTCH1 Up-regulation and Signaling Involved in Mycobacterium bovis BCG-induced SOCS3 Expression in Macrophages^*

From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India

Suppressor of cytokine signaling (SOCS) 3 is a critical negative regulator of cytokine signaling and is induced by Mycobacterium bovis Bacille Calmette-Guérin (M. bovis BCG) in mouse macrophages. However, little is known about the early receptor proximal signaling mechanisms underlying mycobacteria-mediated induction of SOCS3. We demonstrate here for the first time that M. bovis BCG up-regulates NOTCH1 and activates the NOTCH1 signaling pathway, leading to the expression of SOCS3. We show that perturbing Notch signaling in infected macrophages results in the marked reduction in the expression of SOCS3. Furthermore, enforced expression of the Notch1 intracellular domain in RAW 264.7 macrophages induces the expression of SOCS3, which can be further potentiated by M. bovis BCG. The perturbation of Toll-like receptor (TLR) 2 signaling resulted in marked reduction in SOCS3 levels and expression of the NOTCH1 target gene, Hes1. The down-regulation of MyD88 resulted in a significant decrease in SOCS3 expression, implicating the role of the TLR2-MyD88 axis in M. bovis BCG-triggered signaling. However, the SOCS3 inducing ability of M. bovis BCG remains unaltered also upon infection of macrophages from TLR4-defective C3H/HeJ mice. More importantly, signaling perturbation data suggest the involvement of cross-talk among members of the phosphoinositide 3-kinase and mitogen-activated protein kinase cascades with NOTCH1 signaling in SOCS3 expression. Furthermore, SOCS3 expression requires the NOTCH1-mediated recruitment of Suppressor of Hairless (CSL) and nuclear factor-Btothe Socs3 promoter. Overall, these results implicate NOTCH1 signaling during inducible expression of SOCS3 following infection of macrophages with an intracellular bacillus-like M. bovis BCG.

Received for publication, December 6, 2007 , and in revised form, February 19, 2008.

^* This work was supported by the Department of Biotechnology, the Department of Science and Technology (DST), and the Council for Scientific and Industrial Research (CSIR). Infrastructure support was from the ICMR (Center for Advanced Study in Molecular Medicine), DST (Fund for Improvement of Science & Technology Infrastructure in Higher Educational Institutions), and University Grants Commission (special assistance). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S6.

¹ Supported by a fellowship from CSIR, Government of India.

² To whom correspondence should be addressed. Tel.: 91-80-22933223; Fax: 91-80-23602697; E-mail: balaji{at}mcbl.iisc.ernet.in.