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,**
* Center for Biotechnology,
Department of Health Chemistry, School of Pharmaceutical Sciences, and
Department of Oral Anatomy and Developmental Biology, School of Dentistry, Showa University, Tokyo, Japan;
Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan;
¶ Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan;
|| College of Pharmacy, Yeungnam University, Gyonsan, Korea;
# National Cardiovascular Center Research Institute, Osaka, Japan; and
** Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan
We have previously reported that N-myc downstream regulated gene-1 (NDRG1) is an early inducible protein during the maturation of mouse bone marrow-derived mast cells (BMMCs) toward a connective tissue mast cell-like phenotype. To clarify the function of NDRG1 in mast cells and allergic responses, we herein analyzed mast cell-associated phenotypes of mice lacking the Ndrg1 gene. Allergic responses including IgE-mediated passive systemic and cutaneous anaphylactic reactions were markedly attenuated in Ndrg1-deficient mice as compared with those in wild-type mice. In Ndrg1-deficient mice, dermal and peritoneal mast cells were decreased in number and morphologically abnormal with impaired degranulating ability. Ex vivo, Ndrg1-deficient BMMCs cocultured with Swiss 3T3 fibroblasts in the presence of stem cell factor, a condition that facilitates the maturation of BMMCs toward a CTMC-like phenotype, displayed less exocytosis than replicate wild-type cells after the cross-linking of Fc
RI or stimulation with compound 48/80, even though the exocytotic response of IL-3-maintained, immature BMMCs from both genotypes was comparable. Unlike degranulation, the production of leukotriene and cytokines by cocultured BMMCs was unaffected by NDRG1 deficiency. Taken together, the altered phenotypes of Ndrg1-deficient mast cells both in vivo and ex vivo suggest that NDRG1 has roles in the terminal maturation and effector function (degranulation) of mast cells.
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1 This work was supported by a Showa University special grant-in-aid for innovative collaborative research projects and a special research grant-in-aid for development of characteristic education from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. M.M. was supported by Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency.
2 Current address: Department of Immunobiology, School of Pharmaceutical Sciences, Mukogawa Women’s University, Hyogo, Japan.
3 Current address: COE Formation for Genomic Analysis of Disease Model Animals with Multiple Genetic Alterations, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
4 Address correspondence and reprint requests to Dr. Ichiro Kudo, Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, Japan. E-mail address: ichi-ku{at}pharm.showa-u.ac.jp
5 Abbreviations used in this paper: SCF, stem cell factor; NDRG1, N-myc downstream regulated gene-1; BMMC, bone marrow-derived mast cell; CMT4D, Charcot-Marie-Tooth disease type 4D; CPA, carboxypeptidase A; CTMC, connective tissue mast cell; HSA, human serum albumin; 
-HEX, -hexosaminidase; LT, leukotriene; lyso-PS, lysophosphatidyl-L-serine; mMCP, mouse mast cell protease; PCA, passive cutaneous anaphylaxis; PLC, phospholipase C; PMC, peritoneal mast cell.
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