L-selectin and intercellular adhesion molecule-1 regulate the development of Concanavalin A-induced liver injury.
Concanavalin A (Con A)-induced hepatitis is a model for human T cell-mediated hepatitis. We evaluated the role of L-selectin and intercellular adhesion molecule-1 (ICAM-1) in this model by injecting Con A intravenously in mice lacking L-selectin (L-selectin-/-), ICAM-1 (ICAM-1-/-), or both (L-selectin/ICAM-1-/-). Blood and liver samples were collected 0, 8, 24, and 48 h after Con A treatment. Increases in plasma transaminase levels, which peaked 8 h after injection, were reduced significantly in L-selectin-/-, ICAM-1-/-, and L-selectin/ICAM-1-/- mice compared with wild-type mice. Liver necrosis was more strongly inhibited in ICAM-1-/- mice than in L-selectin-/- mice but was most prominently reduced in L-selectin/ICAM-1-/- mice, in parallel with decreased plasma transaminase levels. The reduced severity of hepatitis in the mutant mice correlated with decreases in numbers of liver CD4+ T cells but not numbers of CD8+ T cells or neutrophils. Following Con A treatment, L-selectin deficiency reduced liver mRNA expression of tumor necrosis factor-alpha, and ICAM-1 deficiency reduced expression of interleukin-4. By contrast, reductions in liver macrophage inhibitor protein-1alpha mRNA occurred in all mutant mice. These results indicate that L-selectin and ICAM-1 contribute cooperatively to the development of Con A-induced hepatitis by regulating leukocyte infiltration and subsequent cytokine production.
Kawasuji
Ayako
A
Department of Dermatology, Kanazawa University Graduate School of Medical Science, 13-1, Takara-machi, Kanazawa, 920-8641, Japan.
Hasegawa
Minoru
M
Horikawa
Mayuka
M
Fujita
Tomoyuki
T
Matsushita
Yukiyo
Y
Matsushita
Takashi
T
Fujimoto
Manabu
M
Steeber
Douglas A
DA
Tedder
Thomas F
TF
Takehara
Kazuhiko
K
Sato
Shinichi
S
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003208:Concanavalin A / Q000633:toxicity*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D019041:L-Selectin / Q000235:genetics / Q000276:immunology*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000276:immunology* / Q000293:injuries*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D015291:Transforming Growth Factors / Q000096:biosynthesis
D016207:Cytokines; D012333:RNA, Messenger; D003208:Concanavalin A; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin; D015291:Transforming Growth Factors