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Infection and Immunity, May 2000, p. 2449-2456, Vol. 68, No. 5
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Potentiality of Interleukin-18 as a Useful Reagent for Treatment and Prevention of Leishmania major Infection

Kazunobu Ohkusu,1 Tomohiro Yoshimoto,1,2,3 Kiyoshi Takeda,3,4 Takeharu Ogura,1 Shin-ichiro Kashiwamura,2 Yoichiro Iwakura,5 Shizuo Akira,3,4 Haruki Okamura,2,3 and Kenji Nakanishi1,2,3,*

Department of Immunology and Medical Zoology1 and Laboratory of Host Defenses, Institute for Advanced Medical Sciences,2 Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Department of Host Defenses, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871,4 Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639,5 and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo,3 Japan

Received 3 November 1999/Returned for modification 5 December 1999/Accepted 26 January 2000

Interleukin-18 (IL-18) is a proinflammatory cytokine that plays an important role in natural killer cell activation and the T helper 1 (Th1) cell response, particularly in collaboration with IL-12. Since Th1 cells play a pivotal role in the host defense against infection with intracellular microbes, such as Leishmania major, we investigated whether IL-18 is critically involved in protection against L. major infection by activation of Th1 cells. We administered IL-12 and/or IL-18 daily to L. major-susceptible BALB/c mice. Neither IL-12 (10 ng/mouse) nor IL-18 (1,000 ng/mouse) induced wound healing, while daily injection of IL-12 and IL-18 during the first week after infection strongly protected the mice from footpad swelling by induction and activation of Th1 cells. Furthermore, these mice acquired protective immunity. We also investigated a protective role of endogenous IL-18 by using anti-IL-18 antibody-treated C3H/HeN mice (an L. major-resistant strain) or IL-18 deficient (IL-18-/-) mice with a resistant background (C57BL/6). We found that in the absence of endogenous IL-18, these mice showed prolonged footpad swelling as well as diminished nitric oxide production. However, daily injection of IL-18 into IL-18-/- mice corrected their deficiencies, suggesting that these mice have Th1 cells that produce gamma interferon (IFN-gamma ) in response to IL-18. Indeed, these mice had normal levels of Th1 cells. Thus, IL-18 is not responsible for inducing Th1 cells but participates in host resistance by its action in stimulating Th1 cells to produce IFN-gamma . Our results also indicate the high potentiality of IL-18 as a useful reagent for treatment as well as prevention against reinfection.

* Corresponding author. Mailing address: Department of Immunology and Medical Zoology, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501 Japan. Phone: 81-(798) 45-6573. Fax: 81-(798) 40-5423. E-mail: nakaken{at}hyo-med.ac.jp.

Infection and Immunity, May 2000, p. 2449-2456, Vol. 68, No. 5
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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