title: Role of Fas/Fas ligand-mediated apoptosis in murine contact hypersensitivity.
abstract: Apoptosis plays an important role in immune responses, but little is known about its involvement in contact hypersensitivity (CH). In this study, we have investigated the role of Fas/Fas ligand (FasL)-mediated apoptosis in the pathogenesis of CH. Mice were sensitized by one topical application of 100 microl of 3% oxazolone to shaved skin of the abdomen. Six days later, CH was provoked by challenging both sides of sensitized mouse right ear with 15 microl of 1% oxazolone. Using a DNA ladder assay, we found that apoptosis was induced in the skin of oxazolone-sensitized mice 24-96 h after allergen challenge. Annexin V-fluorescein isothiocyanate (FITC)-propidium iodide (PI) apoptosis flow cytometric assay showed that early apoptotic CD4(+) T cells (annexin V-FITC(+)PI(-)), but not late apoptotic CD4(+) T cells (annexin V-FITC(+)PI(+)), increased in the inflamed skin of mice with CH. Moreover, the expressions of mRNAs for T helper (Th2) cytokine (interleukin (IL)-4), Th1 cytokine (interferon (IFN)-gamma) and proapoptotic molecules (Bax, Fas, FasL and IL-1beta-converting enzyme (ICE)/caspase-1) were significantly elevated in the oxazolone-sensitized mouse skin 6-72 h after allergen challenge. Dramatic increase in IL-10 mRNA was only observed in the sensitized mouse skin 6 and 12 h after allergen challenge. Furthermore, CH was significantly inhibited with decreased apoptosis and early apoptotic CD4(+) T cells in inflamed skin in Fas mutant lpr/lpr mice compared to wild-type mice, whereas there were no significant differences in IL-4, IFN-gamma, IL-10, Bax and ICE mRNAs in the inflamed skin of CH between lpr/lpr and wild-type mice. Our results thus suggest that Fas/FasL pathway partially contributes to apoptosis in murine CH and that Fas/FasL-mediated apoptosis plays a partial role in the development of CH. The contribution of Fas/FasL-mediated apoptosis to CH appears independent of Th1 and Th2 cytokines.
authors.affiliation: Department of Environmental Medicine, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. xubaohui@m.kufm.kagoshima-u.ac.jp
authors.forename: Baohui
authors.initials: B
authors.lastname: Xu
authors.forename: Sivia
authors.initials: S
authors.lastname: Bulfone-Paus
authors.forename: Kohji
authors.initials: K
authors.lastname: Aoyama
authors.forename: Su
authors.initials: S
authors.lastname: Yu
authors.forename: Peixin
authors.initials: P
authors.lastname: Huang
authors.forename: Kanehisa
authors.initials: K
authors.lastname: Morimoto
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsushita
authors.forename: Toru
authors.initials: T
authors.lastname: Takeuchi
mesh_terms: D000276:Adjuvants, Immunologic; D000279:Administration, Cutaneous; D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D020170:Caspase 1 / Q000096:biosynthesis / Q000235:genetics; D053938:DNA Fragmentation / Q000187:drug effects; D003877:Dermatitis, Contact / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D053222:Fas Ligand Protein; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010081:Oxazolone / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; C494827:Bax protein, mouse; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D016753:Interleukin-10; D010081:Oxazolone; D015847:Interleukin-4; D007371:Interferon-gamma; D020170:Caspase 1