Differential and Mutually Exclusive Expression of CD95 and CD95 Ligand in Epithelia of Normal Pancreas and Chronic Pancreatitis

Abstract

SUMMARY:Acinar regression in chronic pancreatitis may be due to immune attack in parenchymal areas neoexpressing HLA-DR molecules. CD4 ϩ 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 Ϫ /CD95L ϩ , ducts were CD95 Ϫ /CD95L Ϫ , and islets were CD95 Ϫ /CD95L ϩ . In areas of lymphohistiocytic infiltration, mainly consisting of CD3 ϩ CD4 ϩ T cells and CD11c ϩ , CD4 ϩ/Ϫ , S100p ϩ interstitial dendritic cells, and in areas of initial fibrosis, acini and ducts were HLA-DR ϩ , acini CD95 ϩ /CD95L Ϫ , and ducts CD95 ϩ /CD95L Ϫ . Islet cells were CD95 Ϫ /CD95L ϩ in both conditions. IFN␥ levels in protein lysates, as measured by an immunoassay, were significantly higher in chronic pancreatitis than in normal pancreas (p Ͻ 0.0003). In vitro, IFN␥ downmodulated 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 Ϫ /CD95L ϩ 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 IFN␥, CD4 ϩ 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. (Lab Invest 2001, 81:317-326).C hronic pancreatitis is characterized by a progressive loss and fibrosis of exocrine parenchyma whereas the endocrine part of the organ remains structurally intact for a prolonged period of time (Bockman, 1997;Klöppel and Maillet, 1993;Sarles, 1991). The disease is often accompanied by duct ectasia and might be initiated by ductal obstruction or distortion (Klöppel and Maillet, 1993). Furthermore, foci of lymphohistiocytic infiltrates are commonly found and are also associated with regressing parenchyma (Bockman, 1997). These infiltrates were shown to contain activated cytotoxic T cells (Hunger et al, 1997), suggesting a role of the immune system in the pathogenesis of acinar atrophy and local scarring. Induction of HLA-DR molecules was observed in parenchymal areas affected by chronic pancreatitis (Bedossa et al, 1990;Jalleh et al, 1993) and transcripts for MCP-1 chemokine have been detected in areas of early stage of chronic pancreatitis (Saurer et al, 2000). Local expression of T cell tropic chemokines may recruit T cell...

Parenchymal regression in chronic pancreatitis spares islets reprogrammed for the expression of NFκB and IAPs

“…Summarizing our previous findings 3,4 and integrating our new data, we propose the following model of CP leading to enforced death of exocrine cells and at the same time to armored survival of endocrine cells ( Figure 5). Initiated by IFNg locally released by CD4 þ Th1 cells, exocrine pancreatic epithelia lose CD95L and neoexpress the functional death receptors CD95, TRAIL-R1 and TRAIL-R2.…”

“…We have previously shown that islets express the deathinducing ligand CD95L (FasL) but do not express its receptor CD95 (Fas). In CP, this 'immunoprivileged' status is preserved in endocrine cells, whereas the exocrine epithelia neoexpress CD95 (Fas) along with HLA-DR. 3 We further showed that islet cells in normal pancreas (NP) are devoid of TRAIL (tumor necrosis factor (TNF)-related apoptosis-inducing ligand) receptors (R), which, like CD95, are members of the TNF receptor superfamily. In CP, there is an induction and high levels of expression of TRAIL-R1, -R2 and -R4 in exocrine cells.…”

In Chronic Pancreatitis, Widespread Emergence of TRAIL Receptors in Epithelia Coincides with Neoexpression of TRAIL by Pancreatic Stellate Cells of Early Fibrotic Areas

“…In CP, TRAIL is induced in scattered exocrine epithelia and pancreatic stellate cells (PSC). Furthermore, TRAIL expression in cultured human PSC is significantly increased by IFN-␥, a potential inflammatory cytokine that we have previously shown to be present at elevated tissue levels in CP (Hasel et al, 2001).…”

“…IFN-␥ and TNF-␣ enhanced TRAIL-R2 mRNA expression in a panel of cancers (Meng and el Deiry, 2001). In CP, tissue concentration of IFN-␥ is increased compared with NP (Hasel et al, 2001). Its most likely source seems to be the lymphohistiocytic infiltrate, which mainly consists of CD3 ϩ CD4 ϩ T cells and CD11c ϩ , CD4 ϩ/Ϫ , S100p ϩ dendritic cells (Hasel et al, 2001).…”

“…We previously showed that the local content of IFN-␥ is significantly increased in CP (Hasel et al, 2001). We therefore stimulated human pancreatic stellate cells (hPSC) for 48 hours with IFN-␥ and analyzed TRAIL mRNA expression by real-time PCR.…”