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1 Center for Surgical Research, University of Alabama at Birmingham, Birmingham, Alabama, United States
2 Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States
3 Surgery, Brigham and Women's Hospital, Boston, Massachusetts, United States
4 Surgery/Immunology, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States
5 Center for Surgical Research, U Alabama at Birmingham, Birmingham, Alabama, United States
* To whom correspondence should be addressed. E-mail: irshad.chaudry{at}ccc.uab.edu.
Although splenic dendritic cell (DC) functions are markedly altered following trauma-hemorrhage, the mechanism(s) responsible for the altered DC functions remains unknown. We hypothesized that trauma-hemorrhage inhibits DC function via suppressing toll-like receptor 4 (TLR4) expression and mitogen-activated protein kinases (MAPKs). To examine this, male C3H/HeN (6-8 weeks) mice were randomly assigned to sham operation or trauma-hemorrhage. Trauma-hemorrhage was induced by midline laparotomy and ~90 min of hypotension (blood pressure (BP) 35 mmHg), followed by fluid resuscitation (4 x the shed blood volume in the form of Ringers lactate). Two hrs later, mice were sacrificed, splenic DCs isolated and the changes in their MAPK activation, TLR4-MD-2 expression, and ability to produce cytokines was measured. The results indicate that trauma-hemorrhage downregulated the lipopolysaccharide (LPS)-induced MAPK activation in splenic DCs. In addition to the decrease in MAPK activation, surface expression of TLR4-MD-2 was suppressed following trauma-hemorrhage. Furthermore, LPS-induced cytokine production from splenic DCs was also suppressed following trauma-hemorrhage. These findings thus suggest that the decrease in TLR4-MD-2 and MAPK activation may contribute to the LPS hyporesponsiveness of splenic DCs following trauma-hemorrhage. Hyporesponsiveness of splenic DCs was also found after stimulation with the TLR2 agonist zymosan. Our results may thus explain the profound immunosuppression that is known to occur under those conditions.
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T. Kawasaki, M. A. Choudhry, M. G. Schwacha, K. I. Bland, and I. H. Chaudry Effect of interleukin-15 on depressed splenic dendritic cell functions following trauma-hemorrhage Am J Physiol Cell Physiol, January 1, 2009; 296(1): C124 - C130. [Abstract] [Full Text] [PDF] |
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