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High mobility group box 1 promotes small intestinal damage induced by nonsteroidal anti-inflammatory drugs through Toll-like receptor 4.
- Source :
-
The American journal of pathology [Am J Pathol] 2012 Jul; Vol. 181 (1), pp. 98-110. Date of Electronic Publication: 2012 May 22. - Publication Year :
- 2012
-
Abstract
- Release of high mobility group box 1 (HMGB1) from damaged cells, which is involved in many types of tissue injuries, activates inflammatory pathways by stimulating multiple receptors, including Toll-like receptor 2 (TLR2), TLR4, and receptor for advanced glycation end-products (RAGE). Our objective was to determine the role of HMGB1 in nonsteroidal anti-inflammatory drug (NSAID)-induced damage of the small intestine. Oral indomethacin (10 mg/kg) induced damage to the small intestine and was associated with increases in intestinal HMGB1 expression and serum HMGB1 levels. In wild-type mice, recombinant human HMGB1 aggravated indomethacin-induced small intestinal damage; enhanced the mRNA expression levels of tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1, and KC; activated nuclear factor kappa B; and stimulated phosphorylation of the mitogen-activated protein kinases p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). In contrast, blocking HMGB1 action with neutralizing antibodies prevented damage and inhibited both inflammatory cytokine overexpression and activation of these intracellular signaling pathways. TLR2-knockout (KO) and RAGE-KO mice exhibited high sensitivities to indomethacin-induced damage, similar to wild-type mice, whereas TLR4-KO mice exhibited less severe intestinal damage and lower levels of TNF-α mRNA expression. Exogenous HMGB1 aggravated the damage in TLR2- and RAGE-KO mice but did not affect the damage in TLR4-KO mice. Thus, our results suggest that HMGB1 promotes NSAID-induced small intestinal damage through TLR4-dependent signaling pathways.<br /> (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cytokines biosynthesis
HMGB1 Protein metabolism
HMGB1 Protein pharmacology
Indomethacin toxicity
Inflammation Mediators metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Peptic Ulcer pathology
Peptic Ulcer physiopathology
Receptor for Advanced Glycation End Products
Receptors, Immunologic physiology
Recombinant Proteins pharmacology
Signal Transduction drug effects
Signal Transduction physiology
Toll-Like Receptor 2 physiology
Toll-Like Receptor 4 deficiency
Anti-Inflammatory Agents, Non-Steroidal toxicity
HMGB1 Protein physiology
Peptic Ulcer chemically induced
Toll-Like Receptor 4 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 181
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 22634181
- Full Text :
- https://doi.org/10.1016/j.ajpath.2012.03.039