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B Cell Lymphoma 10 Is Essential for FcR-Mediated Degranulation and IL-6 Production in Mast Cells¹

Yuhong Chen^2,*, Bhanu P. Pappu^2,, Hu Zeng^*, Liquan Xue, Stephan W. Morris, Xin Lin, Renren Wen^3,* and Demin Wang^3,*,,¶

^* Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226; Department of Molecular and Cellular Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030; Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105; Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226; and ^¶ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, People’s Republic of China

The adaptor protein B cell lymphoma 10 (Bcl10) plays an essential role in the functions of the AgRs in T and B cells. In this study, we report that Bcl10 also plays an important role in mast cells. Bcl10 is expressed in mast cells. Although Bcl10-deficient mast cells undergo normal development, we demonstrate that Bcl10 is essential for specific functions of FcR. Although Bcl10-deficient mast cells have normal de novo synthesis and release of the lipid mediator arachidonic acid, the mutant cells possess impaired FcR-mediated degranulation, indicated by decreased serotonin release, and impaired cytokine production, measured by release of IL-6. In addition, Bcl10-deficient mice display impaired IgE-mediated passive cutaneous anaphylaxis. Moreover, although Bcl10-deficient mast cells have normal FcR-mediated Ca²⁺ flux, activation of PI3K, and activation of the three types of MAPKs (ERKs, JNK, and p38), the mutant cells have markedly diminished FcR-mediated activation of NF-B and decreased activation of AP-1. Thus, Bcl10 is essential for FcR-induced activation of AP-1, NF-B, degranulation, and cytokine production in mast cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grants CA87064 (to S.W.M.), CA21765 (to L.X. and S.W.M.), GM065899 (to X.L.), AI52327 (to R.W.), and HL073284 (to D.W.), and by the American Lebanese Syrian Associated Charities, St. Jude Children’s Research Hospital.

² Y.C. and B.P. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Renren Wen, Blood Research Institute, 8727 Watertown Plank Road, Milwaukee, WI 53226. E-mail address: renren.wen{at}bcw.edu or Dr. Demin Wang, Blood Research Institute, 8727 Watertown Plank Road, Milwaukee, WI 53226. E-mail address: demin.wang{at}bcw.edu

⁴ Abbreviations used in this paper: PLC, phospholipase C; PKC, protein kinase C; HSA, human serum albumin; Bcl10, B cell lymphoma 10; CARD, caspase recruitment domain; CARMA1, CARD membrane-associated guanylate kinase protein 1; MALT, mucosa-associated lymphoid tissue; MALT1, MALT lymphoma translocation protein 1; IKK, IB kinase; MSCV, murine stem cell virus; IRES, internal ribosomal entry site.

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