Neutrophil elastase, MIP-2 and TLR-4 expression during human and experimental sepsis
Abstract:
Highly activated neutrophils play a critical role in mediating organ injury in sepsis by releasing neutrophil elastase (NE). Toll-like receptors (TLRs) play an important role in the host defense against invading microbes, and their signaling pathway is critical to the activation of the proinflammatory response. However, the relationship between TLR expression and the host defense mechanism during sepsis has not been fully elucidated. In this paper, we investigated the relationship between chemokine (MIP-2), TLR-4 and NE expression in human sepsis and in murine peritonitis (CLP).
Methods and Main Results: TLR-4 expression on monocytes/ macrophages was examined in patients with sepsis and in murine peritonitis, and was markedly increased in both populations. LPS-induced MIP-2 production by bronchoalveolar cells and liver mononuclear cells in mice with peritonitis was also significantly increased compared to sham-operated mice. Pretreatment of macrophage cell line, RAW 264.7 cells with a NE inhibitor prior to their exposure to LPS resulted in a significant dose dependent decrease in MIP-2 production, which was comparable to that seen following pretreatment with TLR-4 antibody. Furthermore, NE and LPS both upregulated TLR-4 expression on human peripheral blood monocytes.
Conclusions: Chemokine-induced recruitment of neutrophils in sepsis may result in further increased chemokine production and increased expression of TLR-4. Neutrophil derived NE may be associated with increased expression of monocyte/macrophage TLR-4, thereby serving as a positive feedback loop for the inflammatory response among the different cell populations.
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