Published ahead of print on May 8, 2003, doi:10.1164/rccm.200209-1077OC
Am. J. Respir. Crit. Care Med., Volume 168, Number 2, July 2003, 158-164
A more recent version of this article appeared on July 15, 2003
Submitted on September 20, 2002
Accepted on May 4, 2003
Toll-like receptors-mediated TNF and IL-10 production differ during systemic inflammation
Minou Adib-Conquy1*, Pierre Moine2, Karim Asehnoune3, Alain Edouard3, Terje Espevik4, Kensuke Miyake5, Catherine Werts6, and Jean-Marc Cavaillon1
1 UP Cytokines and Inflammation, Institut Pasteur, Paris, France,
2 Anesthesie Reanimation, Lariboisiere Hospital, Paris, France,
3 Anesthesie Reanimation, Kremlin Bicetre Hospital, Le Kremlin Bicetre, France,
4 Institute of Cancer Research and Molecular Biology, Norweigan University of Science and Technology, Trondheim, Norway,
5 Department of Immunology, Saga Medical School, Saga, Japan,
6 Bacteriologie Moleculaire et Medicale, Institut Pasteur, Paris, France
* To whom correspondence should be addressed. E-mail: madib{at}pasteur.fr.
Major trauma is associated with a decreased capacity of patients' leukocytes to produce pro-inflammatory cytokines upon in vitro stimulation. We studied leukocytes from 44 trauma patients and showed that this hyporeactivity was restricted to Gram-negative bacteria, Escherichia coli endotoxin and unmethylated bacterial DNA, whereas Leptospira interrogans endotoxin-induced tumor necrosis factor (TNF) production was similar to that observed with healthy donors. As well, TNF and interleukin (IL)-6 production in response to Gram-positive bacteria was not altered. The expression of Toll-like receptor (TLR) 2 was not reduced on patients' monocytes as compared to healthy controls, whereas that of TLR4 was reduced. However, the hyporeactivity to Gram-negative bacteria and Escherichia coli endotoxin cannot be fully explained by the downregulation of TLR4. Indeed, unlike pro-inflammatory cytokines, following stimulation with these microbial products the release of anti-inflammatory cytokines was increased as compared to healthy controls. The increased IL-10 production was analyzed in terms of intracellular signaling in peripheral blood mononuclear cells from trauma patients: our results suggest the involvement of p38 mitogen-activated protein kinase, Sp-1 transcription factor, heterotrimeric Gi protein and phosphatidylinositol-3'-kinase. In conclusion, the immunodysregulation described for trauma patients is not a generalized phenomenon, but depends on the stimulus and the signaling pathway.
Key words: lipopolysaccharide, trauma, p38 mitogen-activated protein kinase, TLR9
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