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Pseudomonas aeruginosa-Induced Human Mast Cell Apoptosis Is Associated with Up-Regulation of Endogenous Bcl-x_S and Down-Regulation of Bcl-x_L¹

Department of Microbiology and Immunology and Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada

Mast cells play a critical role in the host defense against bacterial infection. Recently, apoptosis has been demonstrated to be essential in the regulation of host response to Pseudomonas aeruginosa. In this study we show that human mast cell line HMC-1 and human cord blood-derived mast cells undergo apoptosis as determined by the ssDNA formation after infection with P. aeruginosa. P. aeruginosa induced activation of caspase-3 in mast cells as evidenced by the cleavage of D4-GDI, an endogenous caspase-3 substrate and the generation of an active form of caspase-3. Interestingly, P. aeruginosa treatment induced up-regulation of Bcl-x_S and down-regulation of Bcl-x_L. Bcl-x_S, and Bcl-x_L are alternative variants produced from the same Bcl-x pre-mRNA. The former is proapoptotic and the latter is antiapoptotic likely through regulating mitochondrial membrane integrity. Treatment of mast cells with P. aeruginosa induced release of cytochrome c from mitochondria and loss of mitochondrial membrane potentials. Moreover, P. aeruginosa treatment reduced levels of Fas-associated death domain protein-like IL-1-converting enzyme-inhibitory proteins (FLIPs) that are endogenous apoptosis inhibitors through counteraction with caspase-8. Thus, human mast cells undergo apoptosis after encountering P. aeruginosa through a mechanism that likely involves both the Bcl family protein mitochondrial-dependent and the FLIP-associated caspase-8 pathways.

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 by grants from the Canadian Institutes of Health Research, Canadian Cystic Fibrosis Foundation, Nova Scotia Health Research Foundation and Izaak Walton Killam Health Center. T.-J.L. is supported by a New Investigator Award from the Canadian Institutes of Health Research and an Investigatorship from Izaak Walton Killam Health Center.

² Address correspondence and reprint requests to Dr. Tong-Jun Lin, Department of Pediatrics, Izaak Walton Killam Health Center, 5850 University Avenue, Halifax, Nova Scotia B3K 6R8, Canada. E-mail address: tong-jun.lin{at}dal.ca

³ Abbreviations used in this paper used: FLIP, Fas-associated death domain protein-like IL 1-converting enzyme-inhibitory protein; DioC₆, 3,3'-dihexyloxacarbocyanine iodide; CBMC, cord blood-derived mast cell; HMC, human mast cell; BMMC, bone marrow-derived mast cell; MOI, multiplicity of infection.