Anti-apoptotic BFL-1 is the Major Effector in Activation-induced Human Mast Cell Survival

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Jun 22

PMID 22720045

Citations 3

Authors

Maria Ekoff

Katarina Lyberg

Maryla Krajewska

Monica Arvidsson

Sabina Rak

John C Reed

Ilkka Harvima

Gunnar Nilsson

Affiliations

Soon will be listed here.

Abstract

Mast cells are best known for their role in allergic reactions, where aggregation of FcεRI leads to the release of mast cell mediators causing allergic symptoms. The activation also induces a survival program in the cells, i.e., activation-induced mast cell survival. The aim of the present study was to investigate how the activation-induced survival is mediated. Cord blood-derived mast cells and the mast cell line LAD-2 were activated through FcεRI crosslinking, with or without addition of chemicals that inhibit the activity or expression of selected Bcl-2 family members (ABT-737; roscovitine). Cell viability was assessed using staining and flow cytometry. The expression and function of Bcl-2 family members BFL-1 and MCL-1 were investigated using real-time quantitative PCR and siRNA treatment. The mast cell expression of Bfl-1 was investigated in skin biopsies. FcεRI crosslinking promotes activation-induced survival of human mast cells and this is associated with an upregulation of the anti-apoptotic Bcl-2 family member Bfl-1. ABT-737 alone or in combination with roscovitine decreases viability of human mast cells although activation-induced survival is sustained, indicating a minor role for Bcl-X(L), Bcl-2, Bcl-w and Mcl-1. Reducing BFL-1 but not MCL-1 levels by siRNA inhibited activation-induced mast cell survival. We also demonstrate that mast cell expression of Bfl-1 is elevated in birch-pollen-provocated skin and in lesions of atopic dermatitis and psoriasis patients. Taken together, our results highlight Bfl-1 as a major effector in activation-induced human mast cell survival.

Citing Articles

Immunomodulatory Significance of Mast Cell Exosomes (MC-EXOs) in Immune Response Coordination.

Elieh-Ali-Komi D, Shafaghat F, Alipoor S, Kazemi T, Atiakshin D, Pyatilova P Clin Rev Allergy Immunol. 2025; 68(1):20.

PMID: 39976807 PMC: 11842441. DOI: 10.1007/s12016-025-09033-6.

The decoy oligodeoxynucleotide against HIF-1α and STAT5 ameliorates atopic dermatitis-like mouse model.

Gwon M, Leem J, An H, Gu H, Bae S, Kim J Mol Ther Nucleic Acids. 2023; 34:102036.

PMID: 37799329 PMC: 10550406. DOI: 10.1016/j.omtn.2023.102036.

Conditional knockdown of BCL2A1 reveals rate-limiting roles in BCR-dependent B-cell survival.

Sochalska M, Ottina E, Tuzlak S, Herzog S, Herold M, Villunger A Cell Death Differ. 2015; 23(4):628-39.

PMID: 26450454 PMC: 4986635. DOI: 10.1038/cdd.2015.130.

Knockdown of the antiapoptotic Bcl-2 family member A1/Bfl-1 protects mice from anaphylaxis.

Ottina E, Lyberg K, Sochalska M, Villunger A, Nilsson G J Immunol. 2014; 194(3):1316-22.

PMID: 25548219 PMC: 4298126. DOI: 10.4049/jimmunol.1400637.

References

Xiang Z, Moller C, Nilsson G . IgE-receptor activation induces survival and Bfl-1 expression in human mast cells but not basophils. Allergy. 2006; 61(9):1040-6. DOI: 10.1111/j.1398-9995.2006.01024.x. View

Oltersdorf T, Elmore S, Shoemaker A, Armstrong R, Augeri D, Belli B . An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435(7042):677-81. DOI: 10.1038/nature03579. View

MacCallum D, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A . Seliciclib (CYC202, R-Roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res. 2005; 65(12):5399-407. DOI: 10.1158/0008-5472.CAN-05-0233. View

Ishizaka T, Ishizaka K . Activation of mast cells for mediator release through IgE receptors. Prog Allergy. 1984; 34:188-235. View

Nilsson G, Blom T, Harvima I, Kusche-Gullberg M, Nilsson K, Hellman L . Stem cell factor-dependent human cord blood derived mast cells express alpha- and beta-tryptase, heparin and chondroitin sulphate. Immunology. 1996; 88(2):308-14. PMC: 1456426. DOI: 10.1111/j.1365-2567.1996.tb00020.x. View

Yoshikawa H, Nakajima Y, Tasaka K . Glucocorticoid suppresses autocrine survival of mast cells by inhibiting IL-4 production and ICAM-1 expression. J Immunol. 1999; 162(10):6162-70. View

Schendel S, Azimov R, Pawlowski K, Godzik A, Kagan B, Reed J . Ion channel activity of the BH3 only Bcl-2 family member, BID. J Biol Chem. 1999; 274(31):21932-6. DOI: 10.1074/jbc.274.31.21932. View

Galli S . Allergy. Curr Biol. 2000; 10(3):R93-5. DOI: 10.1016/s0960-9822(00)00322-5. View

Dvorak A, Schleimer R, Lichtenstein L . Morphologic mast cell cycles. Cell Immunol. 1987; 105(1):199-204. DOI: 10.1016/0008-8749(87)90068-2. View

10.

Xiang Z, Ahmed A, Moller C, Nakayama K, Hatakeyama S, Nilsson G . Essential role of the prosurvival bcl-2 homologue A1 in mast cell survival after allergic activation. J Exp Med. 2001; 194(11):1561-69. PMC: 2193528. DOI: 10.1084/jem.194.11.1561. View

11.

Barker J . The pathophysiology of psoriasis. Lancet. 1991; 338(8761):227-30. DOI: 10.1016/0140-6736(91)90357-u. View

12.

Diaconu N, Kaminska R, Naukkarinen A, Harvima R, Nilsson G, Harvima I . Increase in CD30 ligand/CD153 and TNF-alpha expressing mast cells in basal cell carcinoma. Cancer Immunol Immunother. 2007; 56(9):1407-15. PMC: 11030587. DOI: 10.1007/s00262-007-0290-7. View

13.

Kawakami T, Galli S . Regulation of mast-cell and basophil function and survival by IgE. Nat Rev Immunol. 2002; 2(10):773-86. DOI: 10.1038/nri914. View

14.

Ortiz-Ferron G, Yerbes R, Eramo A, Lopez-Perez A, De Maria R, Lopez-Rivas A . Roscovitine sensitizes breast cancer cells to TRAIL-induced apoptosis through a pleiotropic mechanism. Cell Res. 2008; 18(6):664-76. DOI: 10.1038/cr.2008.54. View

15.

Tkaczyk C, Okayama Y, Woolhiser M, Hagaman D, Gilfillan A, Metcalfe D . Activation of human mast cells through the high affinity IgG receptor. Mol Immunol. 2002; 38(16-18):1289-93. DOI: 10.1016/s0161-5890(02)00077-9. View

16.

Kirshenbaum A, Akin C, Wu Y, Rottem M, Goff J, Beaven M . Characterization of novel stem cell factor responsive human mast cell lines LAD 1 and 2 established from a patient with mast cell sarcoma/leukemia; activation following aggregation of FcepsilonRI or FcgammaRI. Leuk Res. 2003; 27(8):677-82. DOI: 10.1016/s0145-2126(02)00343-0. View

17.

Raje N, Kumar S, Hideshima T, Roccaro A, Ishitsuka K, Yasui H . Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood. 2005; 106(3):1042-7. PMC: 1895150. DOI: 10.1182/blood-2005-01-0320. View

18.

Metcalfe D, Baram D, Mekori Y . Mast cells. Physiol Rev. 1997; 77(4):1033-79. DOI: 10.1152/physrev.1997.77.4.1033. View

19.

Kobayasi T, ASBOE-HANSEN G . Degranulation and regranulation of human mast cells. An electron microscopic study of the whealing reaction in urticaria pigmentosa. Acta Derm Venereol. 1969; 49(4):369-81. View

20.

Ackermann L, Harvima I . Mast cells of psoriatic and atopic dermatitis skin are positive for TNF-alpha and their degranulation is associated with expression of ICAM-1 in the epidermis. Arch Dermatol Res. 1998; 290(7):353-9. DOI: 10.1007/s004030050317. View