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

Published online before print April 27, 2005

This Article Full Text (Reprint (PDF)) All Versions of this Article: jlb.1204698v1 78/2/565    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Maung, A. A. Articles by Lederer, J. A. Search for Related Content PubMed PubMed Citation Articles by Maung, A. A. Articles by Lederer, J. A.

© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1204698

Received for publication December 2, 2004.
Revised April 1, 2005.
Accepted for publication April 7, 2005.

Article

Enhanced TLR4 reactivity following injury is mediated by increased p38 activation

Adrian A. Maung ^*, Satoshi Fujimi ^*, Marissa L. Miller ^*, Malcolm P. MacConmara ^*, John A. Mannick ^*, and James A. Lederer ^*@

*Department of Surgery (Immunology), Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; and Department of Surgery, Massachusetts General Hospital, Boston

^@ To whom correspondence should be addressed. E-mail: jlederer{at}rics.bwh.harvard.edu.

	Abstract

Severe injury primes the innate-immune system for increased Toll-like receptor 4 (TLR4)-induced proinflammatory cytokine production by macrophages. In this study, we examined changes in TLR4 signaling pathways in splenic macrophages from burn-injured or sham mice to determine the molecular mechanism(s) responsible for the increased TLR4 responsiveness. Using flow cytometry and specific antibodies, we first looked for injury-induced changes in the expression levels of several TLR-associated signaling molecules. We found similar levels of myeloid differentiation primary-response protein 88 and interleukin-1 receptor-associated kinase-M and somewhat lower levels of total p38, extracellular signal-regulated kinase (ERK), and stress-activated protein kinase (SAPK)/c-jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) in burn compared with sham macrophages. However, with the use of antibodies specific for the phosphorylated (activated) forms of the three MAPKs, we found that macrophages from burn mice showed a twofold increase in purified lipopolysaccharide (LPS)-stimulated p38 activation as compared with cells from sham mice on days 1 and 7 post-injury, whereas ERK and SAPK/JNK activation was increased by burn injury only on day 1. Using the specific p38 inhibitor (SB203580), we confirmed that the increase in tumor necrosis factor production by LPS-stimulated burn macrophages requires p38 activation. Although we demonstrated that injury increases macrophage TLR4 mRNA expression and intracellular expression of TLR4-myeloid differentiation protein-2 (MD-2) protein, macrophage cell-surface expression of TLR4-MD-2 was not changed by burn injury. Our results suggest that the injury-induced increase in TLR4 reactivity is mediated, at least in part, by enhanced activation of the p38 signaling pathway.

Key Words: monocytes • macrophages • inflammation • signal transduction

This article has been cited by other articles:

				Y. Tsuda, K. Shigematsu, M. Kobayashi, D. N. Herndon, and F. Suzuki Role of Polymorphonuclear Neutrophils on Infectious Complications Stemming from Enterococcus faecalis Oral Infection in Thermally Injured Mice J. Immunol., March 15, 2008; 180(6): 4133 - 4138. [Abstract] [Full Text] [PDF]

				T. Kawasaki, M. A. Choudhry, M. G. Schwacha, S. Fujimi, J. A. Lederer, K. I. Bland, and I. H. Chaudry Trauma-hemorrhage inhibits splenic dendritic cell proinflammatory cytokine production via a mitogen-activated protein kinase process Am J Physiol Cell Physiol, March 1, 2008; 294(3): C754 - C764. [Abstract] [Full Text] [PDF]

				A. A. Maung, S. Fujimi, M. P. MacConmara, G. Tajima, A. M. McKenna, A. J. Delisle, C. Stallwood, A. B. Onderdonk, J. A. Mannick, and J. A. Lederer Injury Enhances Resistance to Escherichia coli Infection by Boosting Innate Immune System Function J. Immunol., February 15, 2008; 180(4): 2450 - 2458. [Abstract] [Full Text] [PDF]

				T. Suzuki, T. Shimizu, H.-P. Yu, Y.-C. Hsieh, M. A. Choudhry, K. I. Bland, and I. H. Chaudry Estrogen receptor-{alpha} predominantly mediates the salutary effects of 17beta-estradiol on splenic macrophages following trauma-hemorrhage Am J Physiol Cell Physiol, September 1, 2007; 293(3): C978 - C984. [Abstract] [Full Text] [PDF]

				M. T. Bailey, H. Engler, N. D. Powell, D. A. Padgett, and J. F. Sheridan Repeated social defeat increases the bactericidal activity of splenic macrophages through a Toll-like receptor-dependent pathway Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1180 - R1190. [Abstract] [Full Text] [PDF]

				S. Tarang, A. Sodhi, and P. Chauhan Differential expression of Toll-like receptors in murine peritoneal macrophages in vitro on treatment with cisplatin Int. Immunol., May 1, 2007; 19(5): 635 - 643. [Abstract] [Full Text] [PDF]

				T. Kawasaki, M. A. Choudhry, M. G. Schwacha, K. I. Bland, and I. H. Chaudry Lidocaine depresses splenocyte immune functions following trauma-hemorrhage in mice Am J Physiol Cell Physiol, November 1, 2006; 291(5): C1049 - C1055. [Abstract] [Full Text] [PDF]

				B. M. Thobe, M. Frink, M. A. Choudhry, M. G. Schwacha, K. I. Bland, and I. H. Chaudry Src family kinases regulate p38 MAPK-mediated IL-6 production in Kupffer cells following hypoxia Am J Physiol Cell Physiol, September 1, 2006; 291(3): C476 - C482. [Abstract] [Full Text] [PDF]

				B. H. Brownstein, T. Logvinenko, J. A. Lederer, J. P. Cobb, W. J. Hubbard, I. H. Chaudry, D. G. Remick, H. V. Baker, W. Xiao, J. A. Mannick, et al. Commonality and differences in leukocyte gene expression patterns among three models of inflammation and injury Physiol Genomics, February 23, 2006; 24(3): 298 - 309. [Abstract] [Full Text] [PDF]