A mutation in Irak2c identifies IRAK-2 as a central component of the TLR regulatory network of wild-derived mice.
In a phenotypic screen of the wild-derived mouse strain MOLF/Ei, we describe an earlier and more potent toll-like receptor (TLR)-mediated induction of IL-6 transcription compared with the classical inbred strain C57BL/6J. The phenotype correlated with increased activity of the IkappaB kinase axis as well as p38, but not extracellular signal-regulated kinase or c-Jun N-terminal kinase, mitogen-activated protein kinase (MAPK) phosphorylation. The trait was mapped to the Why1 locus, which contains Irak2, a gene previously implicated as sustaining the late phase of TLR responses. In the MOLF/Ei TLR signaling network, IRAK-2 promotes early nuclear factor kappaB (NF-kappaB) activity and is essential for the activation of p38 MAPK. We identify a deletion in the MOLF/Ei promoter of the inhibitory Irak2c gene, leading to an increased ratio of pro- to antiinflammatory IRAK-2 isoforms. These findings demonstrate that IRAK-2 is an essential component of the early TLR response in MOLF/Ei mice and show a distinct pathway of p38 and NF-kappaB activation in this model organism. In addition, they demonstrate that studies in evolutionarily divergent model organisms are essential to complete dissection of signal transduction pathways.
Conner
James R
JR
Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.
Smirnova
Irina I
II
Poltorak
Alexander
A
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D015850:Interleukin-6; D016328:NF-kappa B; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases; D048051:p38 Mitogen-Activated Protein Kinases