Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function.
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.
Adachi
O
O
Department of Biochemistry, Hyogo College of Medicine, Nishinomiya, Japan.
Kawai
T
T
Takeda
K
K
Matsumoto
M
M
Tsutsui
H
H
Sakagami
M
M
Nakanishi
K
K
Akira
S
S
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D018390:Gene Targeting; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D020382:Interleukin-18; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic; D018417:Th1 Cells / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; D007375:Interleukin-1; D020382:Interleukin-18; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011506:Proteins; D011971:Receptors, Immunologic; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases