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J. Biol. Chem., Vol. 280, Issue 21, 20879-20886, May 27, 2005

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The Keratan Sulfate Disaccharide Gal(6S03) 1,4-GlcNAc(6S03) Modulates Interleukin 12 Production by Macrophages in Murine Thy-1 Type Autoimmune Disease^*

Heping Xu, Hitoshi Kurihara, Tomomi Ito, Hiroshi Kikuchi, Keiichi Yoshida¶, Hiroko Yamanokuchi, and Akira Asari||

From the Seikagaku Corporation, 1-5, Nihonbashi-honcho 2-chome, Chuo-ku, Tokyo 103-0023, Japan, the Department of Ophthalmology, University of Aberdeen Medical School, Foresterhill, Aberdeen AB25 2ZD, United Kingdom, and ^¶Mizutani Foundation for Glycoscience, Suite 5F, Sen-i Kaikan, 3-1-11 Nihonbashi-honcho, Chuo-ku, Tokyo 103-0023, Japan

It has been reported that disaccharides of the glycosaminoglycans (GAGs), heparin, or heparan sulfate suppress the production of cytokines. Therefore, we examined the effects of GAGs (keratan sulfate, hyaluronan, chondroitin, chondroitin sulfate, and heparin sulfate) disaccharides on production of interleukin (IL)-12, a pivotal cytokine in the Th-1 type immune system. Among the GAG disaccharides, only a keratan sulfate disaccharide, Gal(6-SO₃)-GlcNAc(6-SO₃) (L4), suppressed IL-12 production in macrophages stimulated with lipopolysaccharides and interferon-. Neither keratan sulfate chains nor keratan sulfate tetrasaccharides elicited any change in the IL-12 production. N-Acetyl-lactosamine, Gal-GlcNAc (LacNAc), also did not change IL-12 production. These results indicated that a certain size, i.e. disaccharide and sulfate, are essential to suppress IL-12 production. L4 was then applied to MRL-lpr/lpr mice, a Th-1 type autoimmune disease model. The treatment of MRL-lpr/lpr mice with L4 1) decreased in serum IL-12, 2) induced apoptosis in T cells in lymph nodes thereby suppressing lymphoaccumulation, and 3) suppressed hypergammaglobulinemia and glomerulonephritis. We showed previously that IL-12 suppresses cell death of T cells, thereby enhancing the lymphoaccumulation in MRL-lpr/lpr mice. Moreover, it has been reported that IL-12 deficiency in MRL-lpr/lpr mice diminishes lymphoaccumulation and delays glomerulonephritis. The treatment with L4 suppressed phosphoprotein kinase C and phosphoinositide 3-kinase expression in macrophages, suggesting that L4 suppresses IL-12 production by inhibiting phosphoprotein kinase C and phosphoinositide 3-kinase pathways.

Received for publication, October 21, 2004 , and in revised form, March 2, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence and reprint requests should be addressed: Seikagaku Corp., 1-5, Nihonbashi-honcho 2-chome, Chuo-ku, Tokyo 103-0023, Japan. Tel.: 81-3-3270-0242; Fax: 81-3-3270-0310; E-mail: aaquira{at}hotmail.com.

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