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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1289-1298
IMMUNOBIOLOGY
Interleukin 18 (IL-18) in synergy with IL-2 induces lethal lung
injury in mice: a potential role for cytokines, chemokines, and
natural killer cells in the pathogenesis of interstitial
pneumonia
Masaki Okamoto,
Seiya Kato,
Kotaro Oizumi,
Masaharu Kinoshita,
Yoshimasa Inoue,
Katsuaki Hoshino,
Shizuo Akira,
Andrew N. J. Mckenzie,
Howard A. Young, and
Tomoaki Hoshino
From the Department of Internal Medicine 1 and the
Department of Pathology, Kurume University School of Medicine,
Japan; R&D Laboratories, Research and Development Division,
Nippon Organon, Osaka, Japan; Department of Host Defense,
Research Institute for Microbial Diseases, Osaka University, Japan;
CREST of Japan Science and Technology Corporation, Suita, Japan;
Medical Research Council Laboratory of Molecular Biology,
Cambridge, United Kingdom; and Laboratory of Experimental
Immunology, National Cancer Institute-Frederick, MD.
Interleukin 18 (IL-18) was discovered as an interferon-
(IFN-)-inducing factor and plays important roles in natural
killer (NK) cell activation. IL-18 also induces proinflammatory
cytokines; chemokines; helper T-cell 2 (TH2) cytokines (eg,
IL-4, IL-13); and immunoglobulin E (Ig-E) and IgG1 production. The
combination of IL-18 plus IL-2 or IL-12 up-regulates IFN- gene
expression and NK cytotoxicity and has synergistic antitumor activity
in vivo and in vitro. Here it is reported that daily
administration of IL-18 with IL-2, but not of IL-18 or IL-2 alone,
induces lethal lung injury in normal mice, but not in IL-18 receptor
 (IL-1 receptor-related protein)-deficient (IL-18 receptor
 /) mice. Marked interstitial infiltration of
lymphocytes, composed mainly of NK cells, was found in the lungs of
IL-18/IL-2-treated mice. Increased cytokine and chemokine levels were
observed in the sera and lungs of IL-18/IL-2-treated mice.
Administration of IL-18/IL-2 was also lethal to mice treated with a
metalloproteinase inhibitor, which inhibited tumor necrosis factor-
and Fas-ligand release. While IFN-/ mice were
partially resistant to the treatment, IL-4/,
IL-13/, IL-4/IL-13/, and
Stat6/ mice were sensitive to IL-18/IL-2, indicating
that these genes were not involved in the host response. The lethal
effect by IL-18/IL-2 was completely eliminated in severe combined
immunodeficient mice pretreated with antiasialo-GM1 antibody and normal
mice pretreated with anti-NK1.1 but not with anti-CD4 or anti-CD8,
monoclonal antibody. These results suggest that specific cytokines,
chemokines, and NK cells are involved in the pathogenesis of
interstitial pneumonia. These results suggest that the clinical use of
this interleukin may result in unexpected physiological consequences.
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