Originally published online as doi:10.1189/jlb.1204698 on April 27, 2005
Published online before print April 27, 2005
(Journal of Leukocyte Biology. 2005;78:565-573.)
© 2005
by Society for Leukocyte Biology
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*,1
* Department of Surgery (Immunology), Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; and
Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts
1 Correspondence: Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115. E-mail: jlederer{at}rics.bwh.harvard.edu
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 (MyD88) and interleukin-1 receptor-associated kinase-M (IRAK-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]
|
|
|
Copyright © 2005 by the Society for Leukocyte Biology.
