Mellett, Mark and Atzei, Paola and Jackson, Ruaidhri and O’Neill, Luke A. and Moynagh, Paul N. (2011) Mal Mediates TLR-Induced Activation of CREB and Expression of IL-10. Journal of Immunology, 186 (8). pp. 4925-4935. ISSN 0022-1767

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Abstract

TLRs initiate immune responses by direct detection of molecular motifs that distinguish invading microbes from host cells. Five intracellular adaptor proteins, each containing a Toll/IL-1R (TIR) domain, are used by TLRs and play key roles in dictating gene expression patterns that are tailored to the invader. Such gene expression is mediated by transcription factors, and although TIR adaptor-induced activation of NF-kB and the IFN regulatory factors have been intensively studied, there is a dearth of information on the role of TIR adaptors in regulating CREB. In this paper, we describe a role for the TIR adaptor Mal in enhancing activation of CREB. Mal-deficient murine bone marrow-derived macrophages show a loss in responsiveness to TLR2 and TLR4 ligands with respect to activation of CREB. Mal-deficient cells also fail to express the CREB-responsive genes IL-10 and cyclooxygenase 2 in response to Pam2Cys-Ser-(Lys)4 and LPS. We reveal that Mal-mediated activation of CREB is dependent on Pellino3 and TNFR-associated factor 6, because CREB activation is greatly diminished in Pellino3 knockdown cells and TNFRassociated factor 6-deficient cells. We also demonstrate the importance of p38 MAPK in this pathway with the p38 inhibitor SB203580 abolishing activation of CREB in murine macrophages. MAPK-activated protein kinase 2 (MK2), a substrate for p38 MAPK, is the likely downstream mediator of p38 MAPK in this pathway, because Mal is shown to activate MK2 and inhibition of MK2 decreases TLR4-induced activation of CREB. Overall, these studies demonstrate a new role for Mal as a key upstream regulator of CREB and as a contributor to the expression of both pro- and anti-inflammatory gene

Item Type:	Article
Additional Information:	The definitive version of this article is available at www.jimmunol.org/cgi/doi/10.4049/jimmunol.1002739
Keywords:	Mal; TLR-Induced Activation; CREB; Expression; IL-10; immune responses; Institute of Immunology; National University of Ireland Maynooth;
Academic Unit:	Faculty of Science and Engineering > Biology Faculty of Science and Engineering > Research Institutes > Institute of Immunology
Item ID:	4280
Depositing User:	Professor Paul Moynagh
Date Deposited:	27 Mar 2013 17:17
Journal or Publication Title:	Journal of Immunology
Publisher:	American Association of Immunologists
Refereed:	Yes
URI:	http://www.jimmunol.org/
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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