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Essential function for the kinase TAK1 in innate and adaptive immune responses

Abstract

Transforming growth factor-β–activated kinase 1 (TAK1) has been linked to interleukin 1 receptor and tumor necrosis factor receptor signaling. Here we generated mouse strains with conditional expression of a Map3k7 allele encoding part of TAK1. TAK1-deficient embryonic fibroblasts demonstrated loss of responses to interleukin 1β and tumor necrosis factor. Studies of mice with B cell–specific TAK1 deficiency showed that TAK1 was indispensable for cellular responses to Toll-like receptor ligands, CD40 and B cell receptor crosslinking. In addition, antigen-induced immune responses were considerably impaired in mice with B cell–specific TAK1 deficiency. TAK1-deficient cells failed to activate transcription factor NF-κB and mitogen-activated protein kinases in response to interleukin 1β, tumor necrosis factor and Toll-like receptor ligands. However, TAK1-deficient B cells were able to activate NF-κB but not the kinase Jnk in response to B cell receptor stimulation. These results collectively indicate that TAK1 is key in the cellular response to a variety of stimuli.

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Figure 1: Establishment of Map3k7−/− MEFs.
Figure 2: Impaired responses to IL-1β and TNF in Map3k7−/− MEFs.
Figure 3: Impaired activation of NF-κB and MAPKs in response to IL-1β and TNF in TAK1-deficient cells.
Figure 4: B cell development in Cd19Cre/+Map3k7flox/− mice.
Figure 5: Impaired B cell activation in response to TLR ligands in Cd19Cre/+Map3k7flox/− mice.
Figure 6: Impaired B cell activation by crosslinking of BCRs in Cd19Cre/+Map3k7flox/− mice.
Figure 7: Impaired immune responses in Cd19Cre/+Map3k7flox/− mice.

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Acknowledgements

We thank R.C. Rickert (The Burnham Institute, La Jolla, California) for providing Cd19-Cre mice; J. Miyazaki (Osaka University, Suita, Japan) for providing CAG-Cre mice; T. Kitamura (University of Tokyo, Tokyo, Japan) for providing retrovirus vector; D.T. Golenbock (University of Massachusetts Medical School, Worcester, Massachusetts) for providing NF-κB reporter; T. Kaisho and Y. Kumagai for discussions; K. Nakamura for cell sorting; A. Shibano, M. Shiokawa, Y. Fujiwara and N. Kitagaki for technical assistance; and M. Hashimoto and E. Horita for secretarial assistance. Supported by Special Coordination Funds, the Ministry of Education, Culture, Sports, Science and Technology.

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Correspondence to Shizuo Akira.

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Supplementary information

Supplementary Fig. 1

Gene targeting of Mapk37. (PDF 198 kb)

Supplementary Fig. 2

Generation of B cell-specific TAK1-deficient mice. (PDF 221 kb)

Supplementary Fig. 3

Proliferation of follicular and marginal zone B cells. (PDF 74 kb)

Supplementary Fig. 4

Immunoblot analysis for p27kip1 and cyclin D2 in Mapk37−/− B cells. (PDF 133 kb)

Supplementary Table 1

Cell cycle and/or proliferation-associated genes altered in BCR-stimulated B cells. (PDF 42 kb)

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Sato, S., Sanjo, H., Takeda, K. et al. Essential function for the kinase TAK1 in innate and adaptive immune responses. Nat Immunol 6, 1087–1095 (2005). https://doi.org/10.1038/ni1255

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