TLR4 Monoclonal Antibody Blockade Suppresses Dextran-Sulfate-Sodium-Induced Colitis in Mice

J Gastroenterol Hepatol. 2010 Jan;25(1):209-14. doi: 10.1111/j.1440-1746.2009.06046.x. Epub 2009 Nov 19.

Abstract

Background and aim: Ulcerative colitis (UC) refers to a kind of inflammatory bowel disease, of which the accurate pathogenesis is not yet well understood. Recently, the toll-like receptor 4 (TLR4) and the TLR4 signaling pathway have been proved as playing an important role in the pathogenesis of UC. The objective of this study was to evaluate the effect of TLR4 monoclonal antibody on dextran-sulfate-sodium-induced colitis in a mouse model.

Methods: We evaluated the effects of the TLR4 monoclonal antibody (TLR4mAb) on the development of dextran-sulfate-sodium-(DSS)-induced colitis. Tissue samples were evaluated by the disease activity index and histopathological score. Meanwhile, the mucosal mRNA expression of cytokines, tumor necrosis factor-alpha, interferon-gamma and interleukin-1beta were analyzed by semiquantitative reverse transcription polymerase chain reaction. The mucosal protein P38-MAPK, c-jun and c-fos expressions of the TLR4-P38MAPK pathway were analyzed using Western blot.

Results: After the treatment with TLR4mAb against DSS-induced colitis, the bodyweight was significantly increased and both disease activity index and histopathological score were decreased significantly. Furthermore, the mucosal expression of messenger RNA of tumor necrosis factor-alpha, interferon-gamma and interleukin-1beta were observed to be 8-15-fold more than the baseline, whereas the mucosal expressions of P38MAPK and c-jun were found to be decreased.

Conclusion: Blocking TLR4 by TLR4mAb can prevent the development of DSS-induced colitis through the TLR4-P38MAPK-c-jun pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Blotting, Western
  • Body Weight / drug effects
  • Colitis / chemically induced
  • Colitis / immunology
  • Colitis / pathology
  • Colitis / prevention & control*
  • Colon / drug effects*
  • Colon / immunology
  • Colon / pathology
  • Dextran Sulfate
  • Disease Models, Animal
  • Interferon-gamma / genetics
  • Interleukin-1beta / genetics
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Severity of Illness Index
  • Signal Transduction / drug effects
  • Toll-Like Receptor 4 / antagonists & inhibitors*
  • Toll-Like Receptor 4 / immunology
  • Tumor Necrosis Factor-alpha / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antibodies, Monoclonal
  • Interleukin-1beta
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Dextran Sulfate
  • p38 Mitogen-Activated Protein Kinases