Issn Print: 0265-0215

Publication Date: 2007/06/01


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Upregulation of TLR2 and LPS receptor TLR4 in septicemic patients: 12AP3-5

T. Munster; S. Kunkele; A. Pahl

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Background and Goal of Study: Sepsis is a systemic response to a generalized infection leading to multiple organ dysfunction. Hyporesponsiveness towards lipopolysaccharide (LPS) has been claimed to contribute to disease progression. Recent data indicate that members of the transmembrane toll-like receptor (TLR) family, called TLR2 and TLR4, are involved in LPS signalling. These receptors are necessary for LPS-signalling and endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface TLR4 expression. Therefore we investigated the expression of proinflammatory cytokines and TLRs during sepsis.
Materials and Methods: After approval of the local Ethics Committee and signed consent we studied septic patients and healthy subjects. Septic patients were enrolled within 24 hours after meeting criteria for diagnosis (1). Blood samples were collected on days 1, 3, 7, 10 and 14. PBMCs from blood samples of sepsis patients were prepared. RNA was prepared from either LPS stimulated or unstimulated monocytes. The mRNA levels of IL1β, IL-6 and TNF and of TLR2 and TLR4 were determined by quantitative real-time RT-PCR.
Results and Discussion: We measured IL-6 and TNFα mRNA level in PBMCs of septic patients compared to healthy controls. TNFα mRNA level were significantly elevated in septic patients. Transcript levels of both TLRs were elevated significantly in septic patients compared to healthy donors. We could not detect LPS tolerance ex vivo in our study population. TLR2 and TLR4 mRNA level from PBMCs of healthy donors treated in vitro with LPS did not reach mRNA levels of untreated PBMCs from septic patients. Therefore an unknown mechanism must account for elevated TLR2 and TLR4 levels in septic patients. Correlations with clinical parameters demonstrate the possible use of TLR2 and TLR4 as new diagnostic markers for the outcome of sepsis.
Conclusion: The upregulation of TLR2 and TLR4 in human patients may contribute to the pathophysiology of sepsis and may result in a self perpetuating cycle leading to septic shock. Interference of this vicious cycle may lead to new therapeutic options for the treatment of sepsis.
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