Toll-Like Receptor 2 and 4 Expression After Severe Injury is Not Involved in the Dysregulation of the Innate Immune System

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Abstract
Severe injury after trauma is associated with a diminished production of different proinflammatory cytokines after stimulation with bacterial cell wall components. The cellular mechanisms, leading to a decreased responsiveness especially of monocytes after multiple injuries have not yet been elucidated in detail. The expression of Toll-like receptors (TLR) on leukocytes is essential for recognition of bacterial components. We investigated the expression of TLR2 and 4 in correlation with gram-negative and gram-positive stimuli-dependent cytokine liberation after severe injury in comparison with that in healthy volunteers. In a prospective clinical experimental study, 12 trauma patients with an Injury Severity Score above 21 points and 14 healthy volunteers were analyzed. Heparinized whole blood samples of patients were collected within 48 hours after trauma and incubated in vitro with or without lipopolysaccharide (LPS) and peptidoglycan (PGN). TLR2 and TLR4 expression on monocytes was analyzed by flow cytometry. LPS- and PGN-induced tumor necrosis factor alpha (TNFalpha) and interleukin-8 production was measured by means of enzyme-linked immunosorbent assay. Both LPS- and PGN-induced TNFalpha liberation were significantly reduced in severely injured patients. The surface expression of TLR2 was also significantly decreased on monocytes collected from trauma patients, whereas the expression of TLR4 remained unchanged. There was only a negative correlation between TLR2 expression and the liberation of TNFalpha after stimulation with LPS or PGN. We conclude that diminished cytokine production after trauma cannot be explained simply by changes in TLR2 or TLR4 expression and that subsequent signaling cascades or additional receptors are involved in the blunted cytokine response after trauma.