Critical role of toll-like receptors and the common TLR adaptor, MyD88, in induction of granulomas and liver injury
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Authors
Velayudham, ArumugamHritz, Istvan
Dolganiuc, Angela
Mandrekar, Pranoti
Kurt-Jones, Evelyn A.
Szabo, Gyongyi
UMass Chan Affiliations
Department of Medicine, Rheumatology DivisionDepartment of Medicine, Division of Gastroenterology
Document Type
Journal ArticlePublication Date
2006-08-29Keywords
Adaptor Proteins, Vesicular TransportAnimals
Blotting, Western
*Gene Expression
Granuloma
Interferon-gamma
Lipopolysaccharides
Liver Diseases
Mice
Mice, Inbred C57BL
Myeloid Differentiation Factor 88
Prognosis
RNA, Messenger
Reverse Transcriptase Polymerase Chain Reaction
Toll-Like Receptors
Gastroenterology
Immunology and Infectious Disease
Metadata
Show full item recordAbstract
BACKGROUND/AIMS: Toll-like receptors (TLR) recognize pathogens and regulate innate immune activation. Here, we investigated the roles of TLR9 and the common TLR adaptor, MyD88, in liver injury. METHODS: C57BL6, TLR9(-/-), IFNgamma(-/-) or MyD88(-/-) mice were primed with Propionibacterium acnes, TLR9 (CpG) or TLR2 (lipoteichoic acid) ligands followed by LPS challenge. ALT, cytokines and liver histology were assessed. RESULTS: Selective priming through TLR9 but not TLR2 induced granulomas, elevated serum ALT, and sensitized C57BL6 mice to increased LPS-induced serum IL-6, IL-12 and IFNgamma levels. Further, TLR2 and TLR9 ligands synergized in induction of granulomas and sensitization to LPS-induced inflammation. IFNgamma induction by P. acnes, TLR2 and TLR9 ligands required MyD88. In MyD88(-/-) mice P. acnes failed to induce granulomas and both MyD88 and TLR9 deficiency prevented P. acnes-induced sensitization to LPS. Increased mRNA expression of genes of the TLR4 signaling complex (TLR4, CD14, MD-2, and MyD88) and the NADPH complexes (p47phox, p67phox, gp91phox, and p22phox) was induced by priming with P. acnes or TLR9 plus TLR2 suggesting mechanisms for LPS sensitization and liver injury. CONCLUSIONS: TLR9+/-TLR2 activation via MyD88-dependent pathways plays a pivotal role in liver sensitization and granuloma formation.Source
J Hepatol. 2006 Dec;45(6):813-24. Epub 2006 Jul 31. Link to article on publisher's siteDOI
10.1016/j.jhep.2006.06.017Permanent Link to this Item
http://hdl.handle.net/20.500.14038/31126PubMed ID
16935388Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.jhep.2006.06.017