Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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-1beta-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.
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PMID:Pseudomonas aeruginosa exotoxin A induces human mast cell apoptosis by a caspase-8 and -3-dependent mechanism. 1520 54

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-1beta-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.
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PMID:Pseudomonas aeruginosa-induced human mast cell apoptosis is associated with up-regulation of endogenous Bcl-xS and down-regulation of Bcl-xL. 1711 73