title: Abnormal expression of Toll-like receptor 4 is associated with susceptibility to ethanol-induced gastric mucosal injury in mice.
abstract: OBJECTIVE
  Toll-like receptor 4 (TLR4) contributes to ethanol-induced gastric mucosal injury. This study aimed to determine its precise role in this pathogenic state and the related signaling pathway.
  
  
  METHODS
  Ethanol-induced gastric mucosal injury models were generated in TLR4(-/-) mice (C3H/HeJ: point mutation; C57BL/10ScNJ: gene deletion), their respective TLR4(+/+) wild-type counterparts, and heterozygous TLR4(+/-) mice. Lipopolysaccharide (LPS) or pyrrolidine dithiocarbamate (PDTC) was injected intraperitoneally 1 h or 30 min before ethanol administration. At 1 h post-ethanol treatment, gastric or serum specimens were evaluated.
  
  
  RESULTS
  Ethanol intra-gastric administration induced significant gastric mucosal injury in all mice, but the damaged area was larger in TLR4(-/-) mice. LPS preconditioning and up-regulated TLR4 expression led to significantly larger areas of gastric mucosal damage. Upon ethanol administration, TLR4(+/+), and not TLR4(-/-), mice showed significant increases in TLR4, myeloid differentiation factor 88 (MyD88), cytoplasmic high mobility group box 1 (HMGB1), and nuclear factor-kappa B p65 (NF-κB p65). PDTC pretreatment significantly attenuated the ethanol-induced gastric mucosal damaged areas, inhibited nuclear NF-κB p65 expression, and suppressed HMGB1 translocation out of the nucleus. In addition, PDTC pretreatment reduced ethanol-stimulated expression of the inflammatory modulators, interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α), in serum.
  
  
  CONCLUSIONS
  Both deficient and excessive expression of TLR4 promotes ethanol-induced gastric mucosal injury. The underlying mechanism involves the MyD88/NF-κB signaling pathway and the HMGB1, TLR4 activator ligand. The increased expression of HMGB1 may lead to increased secretion and binding to TLR4, further stimulating the TLR4/MyD88/NF-κB signaling pathway and aggravating the ethanol-induced gastric mucosal injury.
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, 209 Tongshan Road, Xuzhou, 221002, Jiangsu Province, China, bandye0312@sina.com.
authors.forename: Hui-hui
authors.initials: HH
authors.lastname: Ye
authors.forename: Rong
authors.initials: R
authors.lastname: Hua
authors.forename: Le
authors.initials: L
authors.lastname: Yu
authors.forename: Ke-jian
authors.initials: KJ
authors.lastname: Wu
authors.forename: Su-juan
authors.initials: SJ
authors.lastname: Fei
authors.forename: Xia
authors.initials: X
authors.lastname: Qin
authors.forename: Ying
authors.initials: Y
authors.lastname: Song
authors.forename: Jun-li
authors.initials: JL
authors.lastname: Cao
authors.forename: Yong-mei
authors.initials: YM
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects* / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D024243:HMGB1 Protein / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D013272:Stomach Diseases / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C498144:Rela protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D000431:Ethanol