Impaired mast cell maturation and degranulation and attenuated allergic responses in Ndrg1-deficient mice.
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 FcepsilonRI 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.
Taketomi
Yoshitaka
Y
Center for Biotechnology, Department of Health Chemistry, School of Pharmaceutical Sciences, University, Tokyo, Japan.
Sunaga
Kohei
K
Tanaka
Satoshi
S
Nakamura
Masanori
M
Arata
Satoru
S
Okuda
Tomohiko
T
Moon
Tae-Chul
TC
Chang
Hyeun-Wook
HW
Sugimoto
Yukihiko
Y
Kokame
Koichi
K
Miyata
Toshiyuki
T
Murakami
Makoto
M
Kudo
Ichiro
I
D000707:Anaphylaxis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003594:Cytoplasmic Granules / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005089:Exocytosis / Q000235:genetics / Q000276:immunology; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D016130:Immunophenotyping; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010323:Passive Cutaneous Anaphylaxis / Q000235:genetics / Q000276:immunology; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein