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PMID: 10190904 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice.

The Journal of experimental medicine ·Vol. 189 ·No. 7 ·1999-04-05 ·Pages 1129-38

Kanakaraj P, Ngo K, Wu Y, Angulo A, Ghazal P, Harris CA, Siekierka JJ, Peterson PA, Fung-Leung WP

Abstract

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)-kappaB. 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-kappaB 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.

MeSH Terms
Animals Calcium-Calmodulin-Dependent Protein Kinases/biosynthesis,genetics Cell Differentiation/drug effects Cell Division/drug effects Chimera Crosses, Genetic Cytomegalovirus Infections/immunology Cytotoxicity, Immunologic/drug effects Depression, Chemical Enzyme Activation/drug effects Enzyme Induction/drug effects Female Gene Expression Regulation/drug effects Interferon-gamma/biosynthesis,genetics Interleukin-1 Receptor-Associated Kinases Interleukin-18/pharmacology Interleukin-18 Receptor alpha Subunit Interleukin-4/biosynthesis,genetics JNK Mitogen-Activated Protein Kinases Killer Cells, Natural/immunology Lipopolysaccharides/immunology Lymphocyte Activation/drug effects Male Mice Mice, Inbred C57BL Mice, Knockout Mitogen-Activated Protein Kinases NF-kappa B/metabolism Propionibacterium acnes/immunology Protein Kinases/deficiency,genetics,physiology Receptors, Interleukin/physiology Receptors, Interleukin-18 Signal Transduction/physiology Th1 Cells/cytology,immunology Th2 Cells/cytology,immunology
Chemicals
Il18r1 protein, mouse Interleukin-18 Interleukin-18 Receptor alpha Subunit Lipopolysaccharides NF-kappa B Receptors, Interleukin Receptors, Interleukin-18 Interleukin-4 Interferon-gamma Protein Kinases Interleukin-1 Receptor-Associated Kinases Calcium-Calmodulin-Dependent Protein Kinases JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Kanakaraj P
R.W. Johnson Pharmaceutical Research Institute, San Diego, California 92121, USA.
Ngo K
Wu Y
Angulo A
Ghazal P
Harris C A
Siekierka J J
Peterson P A
Fung-Leung W P
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.189.7.1129
Published
1999-04-05
Pages
1129-38
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193007
Subset
IM
Grants
NIAID NIH HHS · AI30627 · United States
NCI NIH HHS · CA66167 · United States
External Links
PubMed source DOI: 10.1084/jem.189.7.1129 PMC Full Text View journal details
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