Calpain-1 contributes to IgE-mediated mast cell activation.
Mast cells play a central role in allergy through secretion of both preformed and newly synthesized mediators. Mast cell mediator secretion is controlled by a complex network of signaling events. Despite intensive studies, signaling pathways in the regulation of mast cell mediator secretion remain incompletely defined. In this study, we examined the role of calpain in IgE-dependent mast cell activation. IgE-mediated activation of mouse bone marrow-derived mast cells enhanced calpain activity. Inhibition of calpain activity by a number of calpain inhibitors reduced IgE-mediated mast cell degranulation both in vitro and in vivo. Calpain inhibitors blocked IgE-mediated TNF and IL-6 production in vitro and reduced late-phase allergic response in vivo. Importantly, mouse calpain-1 null bone marrow-derived mast cells showed reduced IgE-mediated mast cell degranulation in vitro and in vivo, diminished cytokine and chemokine production in vitro, and impaired late-phase allergic response in vivo. Further studies revealed that calpain-1 deficiency led to specific attenuation of IκB-NF-κB pathway and IKK-SNAP23 pathway, whereas calcium flux, MAPK, Akt, and NFAT pathway proceed normally in IgE-activated calpain-1 null mast cells. Thus, calpain-1 is identified as a novel regulator in IgE-mediated mast cell activation and could serve as a potential therapeutic target for the management of allergic inflammation.
Department of Microbiology and Immunology, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada; Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada;
Zhengli
Z
Wu
Department of Neurology, Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, China;
Xiaochun
X
Chen
Department of Microbiology and Immunology, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada; Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada;
Fang
F
Liu
College of Veterinary Medicine, Jilin University, Changchun, Jilin 130062, China;
Wei
W
Chen
Department of Microbiology and Immunology, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada; Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada;
Ping
P
Wu
Department of Molecular Physiology and Pharmacology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111;
Adam J
AJ
Wieschhaus
Department of Molecular Physiology and Pharmacology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111;
Athar H
AH
Chishti
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and.
Paul A
PA
Roche
Department of Hematology, Fujian Provincial Hospital, Fuzhou, Fujian 350000, China tong-jun.lin@dal.ca chenweiming@medmail.com.cn.
Wei-Min
WM
Chen
Department of Microbiology and Immunology, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada; Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada; tong-jun.lin@dal.ca chenweiming@medmail.com.cn.
Tong-Jun
TJ
Lin
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology* / Q000473:pathology; D002154:Calpain / Q000235:genetics / Q000276:immunology*; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology*; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology; D007073:Immunoglobulin E / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D050766:Qb-SNARE Proteins / Q000235:genetics / Q000276:immunology; D050767:Qc-SNARE Proteins / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
D015850:Interleukin-6; D050778:NFATC Transcription Factors; D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; C107017:Snap23 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D007073:Immunoglobulin E; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D002154:Calpain; C112682:Capn1 protein, mouse