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Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production

Nature Immunology volume 8, pages 57–63 (2007)Cite this article

Abstract

Mice lacking activity of the kinase MEKK1 ('Map3k1ΔKD' mice) have defective activation of the kinase Jnk and increased production of T helper type 2 cytokines after T cell receptor ligation. Here we show that Map3k1ΔKD mice had defective germinal center formation and diminished production of antibodies recognizing thymus-dependent antigens. Those defects were B cell intrinsic, as MEKK1 was necessary for CD40-mediated activation of the kinases Jnk and p38 and transcription factor c-Jun, as well as for expression of cyclin D2 and activation-induced deaminase. MEKK1 was recruited to CD40 and adaptor molecule TRAF2 after CD40 ligation, and Map3k1ΔKD B cells were hypoproliferative after CD40 stimulation. Our data emphasize that MEKK1 is an essential component of signaling cascades needed for thymus-dependent antigen-induced B cell proliferation and antibody production.

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Figure 1: Defective thymus-dependent immune responses in Map3k1ΔKD mice.
Figure 2: Defects in germinal center formation and antibody production are intrinsic to Map3k1ΔKD B cells.
Figure 3: MAPK and NF-κB signaling in Map3k1+/ΔKD and Map3k1ΔKD B cells.
Figure 4: CD40 engagement induces MEKK1 activation, ubiquitination and recruitment to TRAF2.
Figure 5: MEKK1 is required for CD40-mediated activation of AP-1 and Jun and expression of transcripts encoding cyclin D2.
Figure 6: Additional immune defects of Map3k1ΔKD B cells.

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Acknowledgements

Supported by the National Institutes of Health (ES04151 and ES06376 to M.K.), the American Cancer Society (M.K.) and the Leukemia and Lymphoma Society of America (T.E.; SCOR grant 7332-06).

Author information

Author notes

  1. Min Gao

    Present address: Pharmacopeia Drug Discovery, Cranbury, New Jersey, 08512, USA

  2. Ewen Gallagher, Thomas Enzler and Atsushi Matsuzawa: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California San Diego, La Jolla, 92093-0723, California, USA

    Ewen Gallagher, Thomas Enzler, Atsushi Matsuzawa, Ryan Holzer, Min Gao & Michael Karin

  2. Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research, La Jolla, 92037, California, USA

    Amy Anzelon-Mills

  3. Division of Biological Sciences, University of California San Diego, La Jolla, 92093, California, USA

    Dennis Otero

  4. La Jolla Institute for Allergy and Immunology, La Jolla, 92037, California, USA

    Edith Janssen

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Contributions

M.K. designed research and wrote the paper, along with E.G. and T.E.; E.G., T.E. and A.M. did research and analyzed data; A.A. and D.O. helped with flow cytometry and histological analysis; R.H. and M.G. helped with research; and E.J. did the ELISPOT analysis.

Corresponding author

Correspondence to Michael Karin.

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Supplementary information

Supplementary Fig. 1

Histological analysis of CD35+ FDCs in spleens of KLH-immunized mice. (PDF 1854 kb)

Supplementary Fig. 2

CD40-induced proliferation is defective in Map3k1ΔKD B cells. (PDF 536 kb)

Supplementary Fig. 3

CD4+ T cells hyperproliferate in Map3k1ΔKD mice after KLH immunization. (PDF 749 kb)

Supplementary Fig. 4

Jnk2 (Mapk9) but not Jnk1 (Mapk8) is required for B cell proliferation. (PDF 459 kb)

Supplementary Fig. 5

Defective Jnk and p38 MAPK activation in Map3k1ΔKD B cells following stimulation by CD40L or BAFF. (PDF 517 kb)

Supplementary Fig. 6

Immunoprecipitation of endogenous MEKK1. (PDF 605 kb)

Supplementary Fig. 7

Recruitment of MEKK1 to CD40 and TRAF2 following stimulation with CD40L. (PDF 425 kb)

Supplementary Fig. 8

MEKK1 ubiquitination following CD40 engagement. (PDF 586 kb)

Supplementary Fig. 9

Interaction between MEKK1 and TRAFs. (PDF 588 kb)

Supplementary Table 1

Primer sequences used for real-time PCR. (PDF 1155 kb)

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Gallagher, E., Enzler, T., Matsuzawa, A. et al. Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production. Nat Immunol 8, 57–63 (2007). https://doi.org/10.1038/ni1421

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