The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/2000/1/105/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 1, January 3, 2000 105-114

Original Article

Augmentation of V{alpha}14 NKT Cell–mediated Cytotoxicity by Interleukin 4 in an Autocrine Mechanism Resulting in the Development of Concanavalin A–induced Hepatitis

Yoshikatsu Kanekoa, Michishige Haradaa, Tetsu Kawanoa, Masakatsu Yamashitaa, Youichi Shibataa, Fumitake Gejyob, Toshinori Nakayamaa, and Masaru Taniguchia
a From CREST (Core Research for Evolutional Science and Technology) and the Department of Molecular Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
b Department of Internal Medicine, School of Medicine, Niigata University, Niigata 951-8510, Japan

Correspondence to: Masaru Taniguchi, Dept. of Molecular Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Tel:81-43-226-2184 Fax:81-43-227-1498 E-mail:taniguti{at}med.m.chiba-u.ac.jp.

The administration of concanavalin A (Con A) induces a rapid severe injury of hepatocytes in mice. Although the Con A–induced hepatitis is considered to be an experimental model of human autoimmune hepatitis, the precise cellular and molecular mechanisms that induce hepatocyte injury remain unclear. Here, we demonstrate that V{alpha}14 NKT cells are required and sufficient for induction of this hepatitis. Moreover, interleukin (IL)-4 produced by Con A–activated V{alpha}14 NKT cells is found to play a crucial role in disease development by augmenting the cytotoxic activity of V{alpha}14 NKT cells in an autocrine fashion. Indeed, short-term treatment with IL-4 induces an increase in the expression of granzyme B and Fas ligand (L) in V{alpha}14 NKT cells. Moreover, V{alpha}14 NKT cells from either perforin knock-out mice or FasL-mutant gld/gld mice fail to induce hepatitis, and hence perforin–granzyme B and FasL appear to be effector molecules in Con A–induced V{alpha}14 NKT cell–mediated hepatocyte injury.

Key Words: IL-4, V{alpha}14 NKT cell, Con A, hepatitis, autocrine


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