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J. Biol. Chem., Vol. 281, Issue 29, 19872-19880, July 21, 2006

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Chondroitin Sulfate Intake Inhibits the IgE-mediated Allergic Response by Down-regulating Th2 Responses in Mice^*

Shinobu Sakai¹, Hiroshi Akiyama¹², Yuji Sato, Yasuo Yoshioka, Robert J. Linhardt^¶, Yukihiro Goda, Tamio Maitani, and Toshihiko Toida

From the Graduate School of Pharmaceutical Sciences, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan, the National Institute of Health Sciences,1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan, and the ^¶Departments of Chemistry, Biology and Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180

Chondroitin sulfate (CS) was administered orally to BALB/c mice immunized intraperitoneally with ovalbumin (OVA) and/or dinitrophenylated OVA. The titers of antigen-specific IgE and IgG1 in mouse sera were determined. The antigen-specific IgE production by mice fed ad libitum with CS was significantly inhibited. We also examined the effect of feeding CS on immediate-type hypersensitivity. One hour after antigen stimulation, the ears of mice fed with CS swelled less than those of the control mice. Furthermore, the rise in serum histamine in the mice fed with CS under active systemic anaphylaxis was significantly lower than that in the controls. We next examined the pattern of cytokine production by splenocytes from mice followed by re-stimulation with OVA in vitro. The splenocytes from the mice fed with CS produced less interleukin (IL)-5, IL-10, and IL-13 than those from the control group. In contrast, the production of interferon- and IL-2 by the splenocytes of mice fed with CS was not significantly different from those in the control mice. In addition, the production of transforming growth factor- from the splenocytes of mice fed with CS was significantly higher than that of the control mice. Furthermore, we showed that the percentages of CD4⁺ cells, CD8⁺ cells, and CD4⁺CD25⁺ cells in the splenocytes of mice fed with CS are significantly higher than those of the control. These findings suggest that oral intake of CS inhibits the specific IgE production and antigen-induced anaphylactic response by up-regulating regulatory T-cell differentiation, followed by down-regulating the Th2 response.

Received for publication, August 17, 2005 , and in revised form, February 6, 2006.

^* The work was supported in part by grants from the Japan Health Sciences Foundation, the Ministry of Health, Labour and Welfare of Japan, and a Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 81-03-3700-9397; Fax: 81-03-3707-6950; E-mail: akiyama{at}nihs.go.jp.

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