title: Differential and mutually exclusive expression of CD95 and CD95 ligand in epithelia of normal pancreas and chronic pancreatitis.
abstract: Acinar regression in chronic pancreatitis may be due to immune attack in parenchymal areas neoexpressing HLA-DR molecules. CD4+Th1 cytotoxic T cells induce apoptosis of their targets via oligomerizing CD95 (APO-1/Fas) death receptors on target cells by their CD95 ligand (CD95L). We determined the expression of CD95 and CD95L in epithelia of normal and chronically inflamed pancreatic tissues. We applied RT-PCR and Western blotting for CD95L expression profiles, serial frozen section immunohistochemistry to detect CD95, CD95L, and HLA-DR molecules, CD3, CD4, CD11c, and S-100 protein (S100p). Normal pancreases and chronic pancreatitis contain CD95L message and protein. Immunohistochemistry revealed a mutually exclusive expression of CD95 and CD95L. Physiologically, acini were CD95-/CD95L+, ducts were CD95-/CD95L-, and islets were CD95-/CD95L+. In areas of lymphohistiocytic infiltration, mainly consisting of CD3+CD4+ T cells and CD11c+, CD4+/-, S100p+ interstitial dendritic cells, and in areas of initial fibrosis, acini and ducts were HLA-DR+, acini CD95+/CD95L-, and ducts CD95+/CD95L-. Islet cells were CD95-/CD95L+ in both conditions. IFNgamma levels in protein lysates, as measured by an immunoassay, were significantly higher in chronic pancreatitis than in normal pancreas (p < 0.0003). In vitro, IFNgamma down-modulated CD95L message and protein in ASPC1 and BxPc3 pancreatic carcinoma cells. In conclusion, pancreatic epithelia differentially express CD95 and CD95L in a mutually exclusive manner. In chronic pancreatitis the CD95-/CD95L+ status is conserved in islet cells even in the vicinity of lymphohistiocytic infiltrates, whereas it is lost in acini coexpressing HLA-DR. As a potential consequence, and possibly triggered by local release of IFNgamma, CD4-Th1 cells may cognately interact with and successfully attack exocrine cells by triggering CD95 on their target without being killed by epithelial, CD95L-mediated, counterattack.
authors: Departments of Pathology, University of Ulm, Germany.
authors: C
authors: C
authors: Hasel
authors: B
authors: B
authors: Rau
authors: S
authors: S
authors: Perner
authors: J
authors: J
authors: Sträter
authors: P
authors: P
authors: Möller
mesh_terms: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D002908:Chronic Disease; D004847:Epithelial Cells / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D053222:Fas Ligand Protein; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D010179:Pancreas / Q000737:chemistry / Q000473:pathology / Q000502:physiology*; D010195:Pancreatitis / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000032:analysis / Q000235:genetics* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D006684:HLA-DR Antigens; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019014:fas Receptor; D007371:Interferon-gamma