title: 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 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.
authors.affiliation: Department of Surgery I, National Defense Medical College, Tokorozawa, Saitama, 359-8513, Japan. tsuijiflorida@aol.com
authors.forename: Hironori
authors.initials: H
authors.lastname: Tsujimoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ono
authors.forename: Takashi
authors.initials: T
authors.lastname: Majima
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Kawarabayashi
authors.forename: Eiji
authors.initials: E
authors.lastname: Takayama
authors.forename: Manabu
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Shuhji
authors.initials: S
authors.lastname: Seki
authors.forename: Hoshio
authors.initials: H
authors.lastname: Hiraide
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Mochizuki
mesh_terms: D000818:Animals; D001980:Bronchi / Q000166:cytology; D002460:Cell Line; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000096:biosynthesis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D019272:Leukocyte Elastase / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D015846:Monokines / Q000096:biosynthesis*; D010538:Peritonitis / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism; D013997:Time Factors; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015854:Up-Regulation
chemical_list: C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D015846:Monokines; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D019272:Leukocyte Elastase