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¹ Department of Pathology, Tufts University School of Medicine, ² Graduate Program in Immunology, ³ Medical Scientist Training Program, and ⁴ Graduate Program in Genetics, Tufts University Sackler School of Biomedical Sciences, Boston, MA 02111

CORRESPONDENCE Alexander Poltorak: Alexander.Poltorak{at}tufts.edu

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 IB 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 B (NF-B) 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-B 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.

Abbreviations used: BMDM, BM-derived macrophage; cDNA, complementary DNA; EMSA, electromobility shift analysis; ERK, extracellular signal-regulated kinase; IKK, IB kinase; JNK, c-Jun N-terminal kinase; LTA, lipoteichoic acid; MAPK, mitogen-activated protein kinase; MEF, mouse embryonic fibroblast; mRNA, messenger RNA; shRNA, short hairpin RNA; TLR, Toll-like receptor.

© 2009 Conner et al.
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This article has been cited by other articles:

• Conner, J. R., Smirnova, I. I., Poltorak, A. (2009). A mutation in Irak2c identifies IRAK-2 as a central component of the TLR regulatory network of wild-derived mice. JCB 186: i3-i3 [Full Text]  

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