Abstract
MyD88, originally isolated as a myeloid differentiation primary response gene, is shown to act as an adaptor in interleukin-1 (IL-1) signaling by interacting with both the IL-1 receptor complex and IL-1 receptor-associated kinase (IRAK). Mice generated by gene targeting to lack MyD88 have defects in T cell proliferation as well as induction of acute phase proteins and cytokines in response to IL-1. Increases in interferon-gamma production and natural killer cell activity in response to IL-18 are abrogated. In vivo Th1 response is also impaired. Furthermore, IL-18-induced activation of NF-kappaB and c-Jun N-terminal kinase (JNK) is blocked in MyD88-/- Th1-developing cells. Taken together, these results demonstrate that MyD88 is a critical component in the signaling cascade that is mediated by IL-1 receptor as well as IL-18 receptor.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antigens, Differentiation*
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COS Cells
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cells, Cultured
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Cytokines / physiology*
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DNA / metabolism
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Enzyme Activation
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Female
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Gene Targeting
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Humans
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Interleukin-1 / physiology*
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Interleukin-18
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JNK Mitogen-Activated Protein Kinases
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitogen-Activated Protein Kinases*
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Myeloid Differentiation Factor 88
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NF-kappa B / metabolism
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Proteins / genetics
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Proteins / physiology*
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Receptors, Immunologic*
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Th1 Cells / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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Cytokines
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Interleukin-1
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Interleukin-18
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MYD88 protein, human
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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NF-kappa B
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Proteins
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Receptors, Immunologic
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DNA
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases