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J. Biol. Chem., Vol. 279, Issue 35, 37201-37207, August 27, 2004

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Pseudomonas aeruginosa Exotoxin A Induces Human Mast Cell Apoptosis by a Caspase-8 and -3-dependent Mechanism^*

Christopher E. Jenkins, Ania Swiatoniowski, Andrew C. Issekutz, and Tong-Jun Lin¶

From the Departments of Microbiology and Immunology and Pediatrics, Dalhousie University, Halifax, Nova Scotia B3J 3G9, Canada

Mast cells play an important role in both allergy and innate immunity. Recently, we demonstrated an active interaction between human mast cells and Pseudomonas aeruginosa leading to the production of multiple cytokines. Here, we show that both primary cultured human cord blood-derived mast cells and the human mast cell line HMC-1 undergo apoptosis as determined by single-stranded DNA (ssDNA) formation after stimulation with P. aeruginosa exotoxin A (ETA), a major toxin produced by this bacterium. ETA-induced ssDNA formation was completely inhibited by Z-VAD (where Z is benzyloxycarbonyl), which blocks multiple caspases, suggesting a role for caspases in this process. Active caspase-3 formation in mast cells after an ETA challenge was detected by both Western blotting and flow cytometry analysis. ETA-induced caspase-3 activity in human mast cells was demonstrated by the detection of a characteristic 23 kDa product of D4-GDI (where GDI is guanine nucleotide dissociation inhibitor), an endogenous caspase-3 substrate. Interestingly, a specific caspase-8 inhibitor, Z-IETD-fmk (where fmk is fluoromethyl ketone), blocked ETA-induced cleavage of D4-GDI, but a caspase-9 inhibitor (Z-LEHD-fmk) did not. Treatment of mast cells with caspase-3 inhibitor Z-DEVD-fmk or caspase-8 inhibitor Z-IETD-fmk reduced the generation of ssDNA induced by ETA, suggesting a role for caspase-8 and -3 in ETA-induced mast cell apoptosis. Furthermore, treatment of mast cells with ETA induced decreases of the short form and a long form (p43) of Fas-associated death domain protein (FADD)-like interleukin-1-converting enzyme (FLICE) (caspase-8)-inhibitory proteins (FLIPs), which are endogenous caspase-8 inhibitors. Taken together, these results suggest that ETA-induced mast cell apoptosis involves down-regulation of antiapoptotic proteins, FLIPs, and activation of caspase-8 and -3 pathways.

Received for publication, May 19, 2004

^* This work was supported by grants from Canadian Institutes of Health Research, Canadian Cystic Fibrosis Foundation, Nova Scotia Health Research Foundation, and Isaac Walton Killam Health Center. 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.

^¶ Supported by a New Investigator Award from Canadian Institutes of Health Research and an investigatorship from the Isaac Walton Killam Health Center. To whom correspondence should be addressed: I. W. K. Health Center, Dept. of Pediatrics, 5850 University Ave., Halifax, Nova Scotia B3J 3G9, Canada. Tel.: 902-470-8834; Fax: 902-470-7812; E-mail: tong-jun.lin{at}dal.ca.

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