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Gene Review

Map3k14  -  mitogen-activated protein kinase kinase...

Mus musculus

Synonyms: Mitogen-activated protein kinase kinase kinase 14, NF-kappa-beta-inducing kinase, Nik, Serine/threonine-protein kinase NIK, aly
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Disease relevance of Map3k14


High impact information on Map3k14

  • Transgenic complementation with wild-type Nik restored the normal structures of LN, PP, spleen and thymus, and the normal immune response in aly/aly mice [6].
  • The phenotypes of aly/aly mice are more severe than those of Ltbr-/- mice, however, indicating involvement of Nik in signal transduction mediated by other receptors [6].
  • We found that the aly allele carries a point mutation causing an amino acid substitution in the carboxy-terminal interaction domain of Nf-kappa b-inducing kinase (Nik, encoded by the gene Nik) [6].
  • Normal differentiation of thymic MECs requires LTbetaR ligand on thymocytes and LTbetaR together with nuclear factor-kappaB-inducing kinase (Nik) in thymic epithelial cells [7].
  • After stimulation with alpha-GalCer, an antigen recognized by NKT cells, these compound heterozygotes had reduced responses compared with either RelB+/- or aly/+ mice [8].

Biological context of Map3k14

  • In contrast, Nik-/- mice were completely resistant to antigen-induced arthritis (AIA), which requires intact antigen presentation and lymphocyte function but not lymph nodes [9].
  • The 50% lethal dose of L. monocytogenes in aly/aly mice was 10-fold higher than their heterozygotes, termed aly/+mice, or their wild-type C57BL/6 mice [1].
  • Like RelB-deficient mice, aly/aly mice with a mutation for the NF-kappa B-inducing kinase (NIK), have reduced NKT cell numbers [8].
  • We have distinguished defects in LN formation due to failure in embryonic development (aly/aly) from defects in postnatal maturation (Il2rgamma(-/-)Rag2(-/-)) [10].
  • In aly/aly mice, the LN primordium dissipates irreversibly late in gestation; in contrast, Il2rgamma(-/-)Rag2(-/-) LN anlage persists for a week after birth but disperses subsequently, a process reversible by neonatal transfer of WT IL7r(+) TCR(+) T or natural killer (NK) cells, suggesting a role for IL7/IL7r interactions [10].

Anatomical context of Map3k14

  • Nik-/- mice were also resistant to a genetic, spontaneous form of arthritis, generated in mice expressing both the KRN T cell receptor and H-2 [9].
  • Immunodeficiency of alymphoplasia mice (aly/aly) in vivo: structural defect of secondary lymphoid organs and functional B cell defect [11].
  • The aly is a unique spontaneous autosomal recessive mutation in mice that causes a systemic defect of lymph nodes and Peyer's patches [1].
  • In contrast, the complete elimination of bacteria from the spleens and livers of infected mice in the late stage of infection, in which a T-cell-dependent mechanism is required, was delayed in the aly/aly mice [1].
  • The bacterial growth in the spleens and livers of aly/aly mice was more efficient early in infection, and their listericidal activity of peritoneal macrophages was higher than those of aly/+mice [1].

Associations of Map3k14 with chemical compounds

  • Since the aly/aly female cannot lactate, the strain must be bred by intercrossing heterozygous females with homozygous males and the offspring typed by serum IgA levels at the age of 4-6 weeks [12].
  • METHODS: FTY720 was orally administered by gavage (1 mg/kg) to aly/aly mice as well as to aly/+ mice with and without a splenectomy on 14 consecutive days [13].

Other interactions of Map3k14

  • Additionally, transfer of Nik+/+ splenocytes or T cells to Rag2-/- mice conferred susceptibility to AIA, while transfer of Nik-/- cells did not [9].
  • On the key role of secondary lymphoid organs in antiviral immune responses studied in alymphoplastic (aly/aly) and spleenless (Hox11(-)/-) mutant mice [2].
  • To clarify the roles of NIK in T cell activation through TCR/CD3 and costimulation pathways, we have studied the function of T cells from aly mice, a strain with mutant NIK [14].
  • Our results indicate that the aberrant expression of MAdCAM-1 is not the direct cause of aly mutation but rather a secondary defect [15].
  • In the present study, to elucidate the thymic stromal component(s) that affects the development of NK-T cells, radiation bone marrow chimeras were established with the aly/aly mouse as a donor and either the beta2 microglobulin knockout (beta2m-/-) or the CD1d1-/- mouse that also lacks the NK-T cell population as a recipient [16].

Analytical, diagnostic and therapeutic context of Map3k14

  • Since aly/aly spleen cells yielded neutralizing IgM and IgG after adoptive transfer into recipients with normally structured secondary lymphoid organs, these data suggest that the structural defect was mainly responsible for inefficient T-B cooperation [2].
  • We studied the structure of the spleen of aly mice in detail by immunohistochemistry and electron microscopy [17].
  • The results of bone marrow transplantation experiments suggest a mesenchymal disorder as a possible cause of the lack of lymph nodes and of immunodeficiency in the aly mouse [4].
  • The same treatment also prolonged skin allograft survival in aly/aly mice [18].
  • IFN-gamma production in aly/aly spleen cell cultures was recovered in the presence of anti-IL-10 monoclonal antibody (mAb) or recombinant IL-12 [19].


  1. Host resistance against Listeria monocytogenes is reciprocal during the course of infection in alymphoplastic aly mutant mice. Nishikawa, S., Nakane, A. Cell. Immunol. (1998) [Pubmed]
  2. On the key role of secondary lymphoid organs in antiviral immune responses studied in alymphoplastic (aly/aly) and spleenless (Hox11(-)/-) mutant mice. Karrer, U., Althage, A., Odermatt, B., Roberts, C.W., Korsmeyer, S.J., Miyawaki, S., Hengartner, H., Zinkernagel, R.M. J. Exp. Med. (1997) [Pubmed]
  3. aly/aly mice: a unique model of biliary disease. Tsuneyama, K., Kono, N., Hoso, M., Sugahara, H., Yoshida, K., Katayanagi, K., Gershwin, M.E., Saito, K., Nakanuma, Y. Hepatology (1998) [Pubmed]
  4. A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice. Miyawaki, S., Nakamura, Y., Suzuka, H., Koba, M., Yasumizu, R., Ikehara, S., Shibata, Y. Eur. J. Immunol. (1994) [Pubmed]
  5. An accessory role of TCRgammadelta (+) cells in the exacerbation of inflammatory bowel disease in TCRalpha mutant mice. Kawaguchi-Miyashita, M., Shimada , S., Kurosu, H., Kato-Nagaoka, N., Matsuoka, Y., Ohwaki, M., Ishikawa, H., Nanno, M. Eur. J. Immunol. (2001) [Pubmed]
  6. Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase. Shinkura, R., Kitada, K., Matsuda, F., Tashiro, K., Ikuta, K., Suzuki, M., Kogishi, K., Serikawa, T., Honjo, T. Nat. Genet. (1999) [Pubmed]
  7. Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTbetaR. Boehm, T., Scheu, S., Pfeffer, K., Bleul, C.C. J. Exp. Med. (2003) [Pubmed]
  8. NIK-dependent RelB activation defines a unique signaling pathway for the development of V alpha 14i NKT cells. Elewaut, D., Shaikh, R.B., Hammond, K.J., De Winter, H., Leishman, A.J., Sidobre, S., Turovskaya, O., Prigozy, T.I., Ma, L., Banks, T.A., Lo, D., Ware, C.F., Cheroutre, H., Kronenberg, M. J. Exp. Med. (2003) [Pubmed]
  9. NF-(kappa)B-inducing kinase controls lymphocyte and osteoclast activities in inflammatory arthritis. Aya, K., Alhawagri, M., Hagen-Stapleton, A., Kitaura, H., Kanagawa, O., Veis Novack, D. J. Clin. Invest. (2005) [Pubmed]
  10. Role of T and NK cells and IL7/IL7r interactions during neonatal maturation of lymph nodes. Coles, M.C., Veiga-Fernandes, H., Foster, K.E., Norton, T., Pagakis, S.N., Seddon, B., Kioussis, D. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  11. Immunodeficiency of alymphoplasia mice (aly/aly) in vivo: structural defect of secondary lymphoid organs and functional B cell defect. Karrer, U., Althage, A., Odermatt, B., Hengartner, H., Zinkernagel, R.M. Eur. J. Immunol. (2000) [Pubmed]
  12. The donor splice site mutation in NFkappaB-inducing kinase of alymphoplasia (aly/aly) mice. Macpherson, A.J., Uhr, T. Immunogenetics (2003) [Pubmed]
  13. The effect of a novel immunosuppressant, FTY720, in mice without secondary lymphoid organs. Sugito, K., Koshinaga, T., Inoue, M., Ikeda, T., Hagiwara, N., Fukuzawa, M. Surgery today. (2005) [Pubmed]
  14. Essential role of NF-kappa B-inducing kinase in T cell activation through the TCR/CD3 pathway. Matsumoto, M., Yamada, T., Yoshinaga, S.K., Boone, T., Horan, T., Fujita, S., Li, Y., Mitani, T. J. Immunol. (2002) [Pubmed]
  15. Analysis of expression of lymphocyte homing-related adhesion molecules in ALY mice deficient in lymph nodes and Peyer's patches. Koike, R., Watanabe, T., Satoh, H., Hee, C.S., Kitada, K., Kuramoto, T., Serikawa, T., Miyawaki, S., Miyasaka, M. Cell. Immunol. (1997) [Pubmed]
  16. Thymic epithelial cells responsible for impaired generation of NK-T thymocytes in Alymphoplasia mutant mice. Konishi, J., Iwabuchi, K., Iwabuchi, C., Ato, M., Nagata , J.I., Onoé, K., Nakagawa, K.I., Kasai, M., Ogasawara, K., Kawakami, K., Onoé, K. Cell. Immunol. (2000) [Pubmed]
  17. The splenic marginal zone is absent in alymphoplastic aly mutant mice. Koike, R., Nishimura, T., Yasumizu, R., Tanaka, H., Hataba, Y., Hataba, Y., Watanabe, T., Miyawaki, S., Miyasaka, M. Eur. J. Immunol. (1996) [Pubmed]
  18. Analysis of the mode of action of a novel immunosuppressant FTY720 in mice. Luo, Z.J., Tanaka, T., Kimura, F., Miyasaka, M. Immunopharmacology (1999) [Pubmed]
  19. Dysregulation of interleukin-10 and interleukin-12 are involved in the reduced host resistance to Listeria monocytogenes infection in alymphoplastic aly mutant mice. Hasegawa, S., Miura, T., Sasaki, S., Madarame, H., Nakane, A. FEMS Immunol. Med. Microbiol. (2002) [Pubmed]
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