Caspase-dependent and -independent apoptosis of mast cells induced by withdrawal of IL-3 is prevented by Toll-like receptor 4-mediated lipopolysaccharide stimulation.
IL-3-dependent mucosal-like mast cells undergo apoptosis upon withdrawal of IL-3. Generally, the apoptosis is mediated by the activation of caspases and inhibited by addition of the pan-caspase inhibitors z-VAD-FMK or BOC-D-FMK. However, DNA fragmentation, a typical characteristic of apoptosis, is not inhibited by z-VAD-FMK or BOC-D-FMK in mast cell apoptosis. In this study, we demonstrate that the apoptosis of mast cells is mediated by both caspase-dependent and -independent mechanisms. The caspase-independent apoptosis is mediated by the translocation of endonuclease G from mitochondria into nuclei. Withdrawal of IL-3 caused down-regulation of Bcl-xL, resulting in a drop in mitochondrial membrane transition potential followed by the release of cytochrome c and endonuclease G from mitochondria. However, stimulation of mast cells through Toll-like receptor 4 (TLR4) by lipopolysaccharide prevented mast cell apoptosis by inducing expression of Bcl-xL. Moreover, the activation of mast cells by LPS is enhanced in the presence of IFN-gamma, which up-regulates the expression of cell surface TLR4. Taken together, these observations provide evidence that mast cells play important roles not only in allergic reactions but also in innate immunity recognizing enterobacteria through TLR4, and are regulated differently from allergic inflammation by Th1 cytokines.
Yoshikawa
Hideshi
H
Department of Parasitology and Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan. hideshiy@marianna-u.ac.jp
Tasaka
Kachio
K
D021581:Active Transport, Cell Nucleus; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D001593:Benzyl Compounds / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007113:Immunity, Innate; D007377:Interleukin-3 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008564:Membrane Potentials; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D051020:bcl-X Protein
D000590:Amino Acid Chloromethyl Ketones; C494812:Bcl2l1 protein, mouse; D001593:Benzyl Compounds; C476029:Boc-D-FMK; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D006845:Hydrocarbons, Fluorinated; D007377:Interleukin-3; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D051020:bcl-X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D020169:Caspases