MyD88-dependent pathway accelerates the liver damage of Concanavalin A-induced hepatitis.
We have explored the pathological role of the MyD88 signaling pathway via Toll-like receptors (TLRs) that mediate the recognition of pathogen-associated molecular patterns (PAMPs) in a murine model of autoimmune hepatitis induced by administering Concanavalin A (ConA). We first found that various TLRs and MyD88 molecules were expressed in liver of Con A-treated and untreated wild-type (WT) mice including liver macrophages. Flowcytometric analysis revealed that liver CD11b(+)CD11c(-) and CD11b(+)CD11c(+) antigen-presenting cells express TLR2, although NK and NKT cells did not. When WT and MyD88(-/-) mice were intravenously administered with Con A, the severity of hepatitis was significantly lower in Con A-injected MyD88(-/-) mice than in WT mice in terms of the histopathology, the levels of serum transaminase and pro-inflammatory cytokines (TNF-alpha, IFN-gamma, and IL-6), and upregulation of CD80/CD86 and TNF-alpha on/in liver macrophages. The results provide evidence of a possible contribution of the TLRs-MyD88 signaling pathway in activating TLR-expressing liver macrophages in the autoimmune hepatitis model, and thus indicate that the strategy of blockade of pathological pathogens via the intestinal lumen may be feasible for the treatment of the disease.
Ojiro
Keisuke
K
Department of Gastroenterology and Hepatology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Ebinuma
Hirotoshi
H
Nakamoto
Nobuhiro
N
Wakabayashi
Kanji
K
Mikami
Yohei
Y
Ono
Yuichi
Y
Po-Sung
Chu
C
Usui
Shingo
S
Umeda
Rumiko
R
Takaishi
Hiromasa
H
Yamagishi
Yoshiyuki
Y
Saito
Hidetsugu
H
Kanai
Takanori
T
Hibi
Toshifumi
T
D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D003208:Concanavalin A / Q000494:pharmacology; D004195:Disease Models, Animal; D019693:Hepatitis, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha
D018122:B7-1 Antigen; D051940:B7-2 Antigen; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A