Capsular polysaccharide induction of apoptosis by intrinsic and extrinsic mechanisms.
A purified microbial capsular polysaccharide of Cryptococcus neoformans, glucuronoxylomannan (GXM), induces Fas ligand (FasL) upregulation on macrophages and, as a consequence, apoptosis of lymphocytes. The mechanisms that lead to lymphocyte apoptosis in both in vitro and in vivo systems were investigated by cytofluorimetric analysis and Western blotting experiments. Caspase 8 cleaves caspase 3 in two different pathways: directly as well as indirectly by activation of Bcl-2 interacting domain, which initiates caspase 9 cleavage. Therefore, the caspase 8 and caspase 9 pathways cooperate in an amplification loop for efficient cell death, and noteworthily we provide evidence that they are both activated in one single cell. Furthermore, both activation of GXM-mediated caspase 8 and apoptosis were also found in in vivo systems in an experimental model of murine candidiasis. Collectively, our data show that GXM-induced apoptosis involves, in a single cell, a cross-talk between extrinsic and intrinsic pathways. Such a finding offers opportunities for the therapeutic usage of this polysaccharide in appropriate clinical settings for taming T-cell responses.
Monari
Claudia
C
Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
Paganelli
Francesca
F
Bistoni
Francesco
F
Kozel
Thomas R
TR
Vecchiarelli
Anna
A
D000818:Animals; D017209:Apoptosis; D002177:Candidiasis / Q000276:immunology; D053181:Caspase 8 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D003455:Cryptococcus neoformans / Q000276:immunology*; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008954:Models, Biological; D011134:Polysaccharides / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
D011134:Polysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2; C513669:caspase 9s, human; C027478:glucuronoxylomannan; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases