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. 2005 Jan;23(1):39-44.
doi: 10.1097/01.shk.0000145936.31967.d7.

Neutrophil elastase, MIP-2, and TLR-4 expression during human and experimental sepsis

Hironori Tsujimoto  1 , Satoshi Ono, Takashi Majima, Nobuaki Kawarabayashi, Eiji Takayama, Manabu Kinoshita, Shuhji Seki, Hoshio Hiraide, Lyle L Moldawer, Hidetaka Mochizuki
Affiliations

Neutrophil elastase, MIP-2, and TLR-4 expression during human and experimental sepsis

Hironori Tsujimoto et al. Shock. 2005 Jan.

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 relationships among chemokine (MIP-2), TLR-4, and NE expression in human sepsis and murine peritonitis (CLP). 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 with sham-operated mice. Pretreatment of the macrophage cell line, RAW 264.7 cells, with a NE inhibitor before 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 up-regulated TLR-4 expression on human peripheral blood monocytes. Thus, 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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