The Journal of Experimental Medicine
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Published 17 February 2004. doi:10.1084/jem.20031368
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 4, 535-545
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Interleukin 18 Acts on Memory T Helper Cells Type 1 to Induce Airway Inflammation and Hyperresponsiveness in a Naive Host Mouse

Takaaki Sugimoto1, Yuriko Ishikawa2,3, Tomohiro Yoshimoto2,3, Nobuki Hayashi2,3, Jiro Fujimoto1, and Kenji Nakanishi2,3

1 Department of Surgery, Hyogo College of Medicine, Hyogo 663-8501, Japan
2 Department of Immunology and Medical Zoology, Hyogo College of Medicine, Hyogo 663-8501, Japan
3 Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan

Address correspondence to Kenji Nakanishi, Department of Immunology and Medical Zoology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. Phone: 81-798-45-6572; Fax: 81-798-40-5423; email: nakaken{at}hyo-med.ac.jp

Interleukin (IL)-18 was originally regarded to induce T helper cell (Th)1-related cytokines. In general, factors favoring interferon (IFN)-{gamma} production are believed to abolish allergic diseases. Thus, we tested the role of IL-18 in regulation of bronchial asthma. To avoid a background response of host-derived T cells, we administered memory type Th1 or Th2 cells into unsensitized mice and examined their role in induction of bronchial asthma. Administration of antigen (Ag) induced both airway inflammation and airway hyperresponsiveness (AHR) in mice receiving memory Th2 cells. In contrast, the same treatment induced only airway inflammation but not AHR in mice receiving memory Th1 cells. However, these mice developed striking AHR when they were coadministered with IL-18. Furthermore, mice having received IFN-{gamma}–expressing Th1 cells sorted from polarized Th1 cells developed severe airway inflammation and AHR after intranasal administration of Ag and IL-18. Thus, Th1 cells become harmful when they are stimulated with Ag and IL-18. Newly polarized Th1 cells and IFN-{gamma}–expressing Th1 cells, both of which express IL-18 receptor {alpha} chain strongly, produce IFN-{gamma}, IL-9, IL-13, granulocyte/macrophage colony-stimulating factor, tumor necrosis factor {alpha}, regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein 1{alpha} upon stimulation with Ag, IL-2, and IL-18 in vitro. Thus, Ag and IL-18 stimulate memory Th1 cells to induce severe airway inflammation and AHR in the naive host.

Key Words: IL-9 • IL-13 • IL-18 • Th1 • bronchial asthma

T. Sugimoto and Y. Ishikawa contributed equally to this work.

Abbreviations used in this paper: AHR, airway hyperresponsiveness; APC, allophycocyanin; BAL, bronchoalveolar lavage; BALF, BAL fluid; DTH, delayed-type hypersensitivity; Mch, methacholine; MIP, macrophage inflammatory protein; RANTES, regulated on activation, normal T cell expressed and secreted; Tg, transgenic.


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