The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/4/1129/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 7, April 5, 1999 1129-1138

Articles

Defective Interleukin (IL)-18–mediated Natural Killer and T Helper Cell Type 1 Responses in IL-1 Receptor–associated Kinase (IRAK)-deficient Mice

Palanisamy Kanakaraj*, Karen Ngo*, Ying Wu*, Ana Angulo§, Peter Ghazal§, Crafford A. Harris{ddagger}, John J. Siekierka{ddagger}, Per A. Peterson{ddagger}, and Wai-Ping Fung-Leung*

From * R.W. Johnson Pharmaceutical Research Institute, San Diego, California 92121; {ddagger} R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey 08869; and the § Department of Immunology and Molecular Biology, Division of Virology, Scripps Research Institute, La Jolla, California 92037

Interleukin (IL)-18 is functionally similar to IL-12 in mediating T helper cell type 1 (Th1) response and natural killer (NK) cell activity but is related to IL-1 in protein structure and signaling, including recruitment of IL-1 receptor–associated kinase (IRAK) to the receptor and activation of c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-{kappa}B. The role of IRAK in IL-18–induced responses was studied in IRAK-deficient mice. Significant defects in JNK induction and partial impairment in NF-{kappa}B activation were found in IRAK-deficient Th1 cells, resulting in a dramatic decrease in interferon (IFN)-{gamma} mRNA expression. In vivo Th1 response to Propionibacterium acnes and lipopolysaccharide in IFN-{gamma} production and induction of NK cytotoxicity by IL-18 were severely impaired in IRAK-deficient mice. IFN-{gamma} production by activated NK cells in an acute murine cytomegalovirus infection was significantly reduced despite normal induction of NK cytotoxicity. These results demonstrate that IRAK plays an important role in IL-18–induced signaling and function.

Key Words: c-Jun NH2-terminal kinase • inhibitor of nuclear factor {kappa}B • nuclear factor {kappa}B • interferon {gamma} • murine cytomegalovirus

Address correspondence to Wai-Ping Fung-Leung, 3535 General Atomics Ct., Suite 100, R.W. Johnson Pharmaceutical Research Institute, San Diego, CA 92121. Phone: 619-450-2016; Fax: 619-450-2070; E-mail: wleung{at}prius.jnj.com

Abbreviations used: AP-1, activator protein 1; ES, embryonic stem; GST, glutathione S-transferase; ICE, IL-1β converting enzyme; I{kappa}B, inhibitor of NF-{kappa}B; IKK, I{kappa}B kinase; IRAK, IL-1 receptor–associated kinase; JAK, Janus kinase; JNK, c-Jun NH2-terminal kinase; MAP, mitogen-activated protein; MCMV, murine cytomegalovirus; NF, nuclear factor; STAT, signal transducer and activator of transcription; TRAF, TNF receptor–associated factor.


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