Pathophysiological roles of basophils and mast cells in allergic inflammations
| Project/Area Number |
18380176
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Basic veterinary science/Basic zootechnical science
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| Research Institution | Tokyo University of Science |
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Principal Investigator |
GOITSUKA Ryo Tokyo University of Science, Research Institute for Biological Sciences, Professor (50301552)
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| Co-Investigator(Kenkyū-buntansha) |
HAYASHI Tomohito Tokyo University of Science, Research Institute for Biological Sciences, Assistant Professor (90297630)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥17,730,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2007: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2006: ¥8,500,000 (Direct Cost: ¥8,500,000)
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| Keywords | Allergy / mast cells / basophils / IgE receptor / signal transduction |
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| Research Abstract |
Engagement of the high-affinity IgE receptor (FcεRI) on mast cells as well as basophils induces the release of preformed inflammatory mediators by degranulation and also the de novo synthesis and secretion of inflammatory cytokines, leading to an array of acute and chronic allergic symptoms. Two SLP-76 family adaptors, SLP-76 and MIST, are expressed in both mast cells and basophils, and both are involved in FcεRI -signaling. However, the functional redundancy and/or specificity of SLP-76 and MIST in this process remain unclear. In the present study, we intended to clarify the functional redundancy and/or specificity of SLP-76 and MIST in FcεRI-mediated allergic reactions by using mice deficient in MIST and/or SLP-76.
FcεRI-induced degranulation was slightly and profoundly reduced in MIST- and SLP-76-deficient mast cells than in wild type cells, respectively. The residual degranulation detected in SLP-76-deficient cells was completely abrogated by the introduction of a MIST-deficiency. T
… More
o gain insight into the molecular basis for the functional difference between SLP-76 and MIST in FcεRI-signaling, we examined the mode of molecular interactions and membrane targeting of these two adaptors. SLP-76 associated with Grb2-related adaptor downstream of She (Gads) whereas MIST did not. However, when the Grb2-binding motif in MIST was replaced with a high-affinity RXXK SH3-binding motif from SLP-76, this mutant (MIST-GBF) gained the ability to associate with Gads. Although recruitment and cluster formation of wild type MIST at the antigen contact site were weaker than that observed for SLP-76, the MIST GBF mutant behaved like SLP-76 in terms of these FcεRI-induced changes. Furthermore, expression of MIST-GBF in mast cells enhanced FcεRI-mediated degranulation to a level comparable to that observed in SLP-76-expressing cells, indicating that the presence of the Gads-binding motif (RXXK) determines the functional dominance of SLP-76 over MIST in FcεRI-mediated mast cell activation.
Since SLP-76 is constitutively but MIST is inducibly expressed in mast cells and basophils, these two SLP-76 family adaptors function as a basal essential regulator and an amplifier of FcεRI-mediated mast cell activation, respectively, in allergic reactions. Less
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Report
(3 results)
Research Products
(37 results)
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[Journal Article] Distinct regulatory functions of SLP-76 and MIST in NK cell cytotoxicity and IFN-g production2008
Author(s)
Hidano, S., Sasanuma, H., Ohshima, K., Seino, K-I., Kumar, L., Hayashi, K., Hikida, M., Kurosaki, T., Taniguchi, M., Geha, R. S., Kitamura, D., Goitsuka, R
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Author(s)
Saltis, M., Criscitielo, M. F.,Ohta Y., Keefe, M., Trede, N. S., Goitsuka, R. Flajnik, M
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Journal Title
Immunogenetics (in press)
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[Journal Article] IL-7/STAT5 Cytokine Signaling Pathway Is Essential but Insufficient for Maintenance of Naive CD4 T Cell Survival in Peripheral Lymphoid Organs2007
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Seki, Y., Yang, J., Okamoto, M., Tanaka, S., Goitsuka, R., Farrar, M. A., Kubo, M.
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Journal Title
J. Immunol 178(1)
Pages: 262-270
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[Journal Article] Chicken cathelicidin-B1, an antimicrobial guardian at the mucosal M cell gateway2007
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Goitsuka, R., Chen, C. H., Benyon, L., Asano, Y., Kitamura, D., Cooper, M. D
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Journal Title
Proc. Natl. Acad. Sci. USA 104(38)
Pages: 15063-15068
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[Journal Article] Dual function for the adaptor MIST in IFN-g production by NK and CD4+NKT cells regulated by the Src-kinase Fgr2006
Author(s)
Sasanuma, H., Tatsuno, A., Hidano, S., Ohshima, K., Matsuzaki, Y., Hayashi, K., Lowell, C. A., Kitamura, D. Goitsuka, R
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Journal Title
Blood 107(9)
Pages: 3647-3655
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[Journal Article] Double knockout mice show BASH and PKCd have different epistatic relationships in B cell maturation and CD40-mediated activation2006
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Nojima, T., Hayashi, K., Goitsuka, R., Nakayama, K., Nakayama, K.-i. Kitamura, D
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Journal Title
Immunol. Lett 105(1)
Pages: 48-54
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[Journal Article] A novel avian homologue of CD72, chBlr, down modulates BCR-mediated activation signals2006
Author(s)
Fujiwara, N., Hidano, S., Mamada, H., Ogasawara, K., Kitamura, D., Cooper, M.,. D., Hozumi, N., Chen, C., L., Goitsuka, R
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Journal Title
Int. Immunol 18(5)
Pages: 775-783
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[Journal Article] BASH-novel PKC-Raf-1 pathway of pre-BCR signaling induces k gene rearrangement2006
Author(s)
Yamamoto, M., Hayashi, K., Nojima, T., Matsuzaki, Y., Kawano, Y., Karasuyama, H., Goitsuka, R., Kitamura, D
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Journal Title
Blood 108(8)
Pages: 2703-2711
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