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IFNgamma plays an important role to induce several functional molecules on salivary epithelial cells, including class II MHC, Fas and CD40 in salivary glands from patients with Sjogren's syndrome (SS). IFNgamma also contributes to the development of lymphocytic infiltrates by inducing T cell attracting chemokines in SS salivary epithelial cells, such as IP-10 (CXCL10), Mig (CXCL9), and I-TAC (CXCL11). IFNgamma dysregulation in SS salivary gland may attribute to the decreased production of TGFbeta from salivary epithelial cells in some patients. Expression of Fas and CD40 was significantly higher in SS salivary epithelial cells than in normal cells after IFNgamma stimulation. Although neither anti-Fas (CH11) nor anti-CD40 mAb alone could induce typical apoptosis, the two together and preincubation with IFNgamma efficiently induced apoptosis in SS salivary epithelial cells. This apoptosis was almost completely blocked by neutralizing anti-Fas mAb (ZB4). c-FLIP, an important inhibitory molecule in the Fas death pathway, was strongly expressed in SS salivary epithelial cells, but its expression was downregulated, at the protein level, by anti-CD40 mAb. CD40 signals promote Fas-dependent death of SS salivary epithelial cells by downregulating c-FLIP expression. The presence of c-FLIP in these cells may explain their resistance to undergo apoptosis in response to either anti-Fas or anti-CD40 mAb, despite their surface expression of both proteins. These findings suggest that SS salivary epithelial cell death requires the cooperation of Fas and CD40.