Cryptococcus neoformans capsular glucuronoxylomannan induces expression of fas ligand in macrophages.
The major component of capsular material of Cryptococcus neoformans is glucuronoxylomannnan (GXM), a polysaccharide that exhibits potent immunosuppressive properties in vitro and in vivo. The results reported here show that 1) soluble purified GXM induces a prompt, long-lasting, and potent up-regulation of Fas ligand (FasL) on macrophages, 2) the up-regulation of FasL is related to induced synthesis and increased mobilization to the cellular surface, 3) this effect is largely mediated by interaction between GXM and TLR4, 4) FasL up-regulation occurs exclusively in GXM-loaded macrophages, 5) macrophages that show up-regulation of FasL induce apoptosis of activated T cells expressing Fas and Jurkat cells that constitutively express Fas, and 6) anti-Fas Abs rescue T cells from apoptosis induced by GXM. Collectively our results reveal novel aspects of the immunoregulatory properties of GXM and suggest that this nontoxic soluble compound could be used to dampen the immune response, to promote or accelerate the death receptor, and to fix FasL expression in a TLR/ligand-dependent manner. In the present study, we delineate potential new therapeutic applications for GXM that exploit death receptors as key molecular targets in regulating cell-mediated cytotoxicity, immune homeostasis, and the immunopathology of diseases.
Monari
Claudia
C
Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
Pericolini
Eva
E
Bistoni
Giovanni
G
Casadevall
Arturo
A
Kozel
Thomas R
TR
Vecchiarelli
Anna
A
D017209:Apoptosis; D003455:Cryptococcus neoformans / Q000276:immunology*; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D053222:Fas Ligand Protein; D006801:Humans; D007108:Immune Tolerance; D007155:Immunologic Factors / Q000494:pharmacology; D066298:In Vitro Techniques; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000378:metabolism; D011134:Polysaccharides / Q000276:immunology* / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007155:Immunologic Factors; D008562:Membrane Glycoproteins; D011134:Polysaccharides; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D003609:Dactinomycin; C027478:glucuronoxylomannan; D003513:Cycloheximide