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Published online before print February 3, 2006

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(Journal of Leukocyte Biology. 2006;79:696-705.)
© 2006 by Society for Leukocyte Biology

L-selectin and intercellular adhesion molecule-1 regulate the development of Concanavalin A-induced liver injury

Ayako Kawasuji^*, Minoru Hasegawa^*,1, Mayuka Horikawa^*, Tomoyuki Fujita^*, Yukiyo Matsushita^*, Takashi Matsushita^*, Manabu Fujimoto^*, Douglas A. Steeber, Thomas F. Tedder, Kazuhiko Takehara^* and Shinichi Sato

^* Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan;
Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin;
Department of Immunology, Duke University Medical Center, Durham, North Carolina; and
Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

¹Correspondence: Department of Dermatology, Kanazawa University Graduate School of Medical Science, 13-1, Takara-machi, Kanazawa, 920-8641, Japan. E-mail: minoruha{at}derma.m.kanazawa-u.ac.jp

ABSTRACT

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-, and ICAM-1 deficiency reduced expression of interleukin-4. By contrast, reductions in liver macrophage inhibitor protein-1 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.

Key Words: hepatitis • cytokine • animal model