Fas and Fas-mediated effects on a human salivary cell line in vitro: a model for immune-mediated exocrine damage in Sjögren's syndrome

Abstract

Sjo È gren's syndrome (SS) is an autoimmune exocrinopathy characterized by mononuclear cell infiltration and loss of parenchymal tissue in salivary and lacrimal glands. The mechanisms for these histologic alterations are not known. Apoptotic cell death, induced by the ligation of Fas (APO-1/ CD95) with Fas ligand (FasL/CD95L) may be an explanation for the tissue damage seen in SS. Fas and FasL were detected in minor salivary glands from SS patients and healthy individuals using immunohistochemical methods. There was increased expression of both Fas and FasL in the patients. The ability of the Fas-FasL pathway to influence epithelial cell growth and survival was demonstrated in vitro using a human submandibular cell line. The presence of Fas receptor was demonstrated on the cells. Anti-Fas antibody triggered cell death. Cells were also grown in the presence of gammainterferon (IFN-g). IFN-g induced an upregulation of Fas receptor expression and pre-treatment of cells with IFN-g led to enhanced anti-Fas mediated cell death.

Induction of Salivary Gland Epithelial Cell Injury in Sjogren's Syndrome: In Vitro Assessment of T Cell-derived Cytokines and Fas Protein Expression

“…Several studies have indicated that IFN-increases the sensitivity to anti-Fas mAb, likely through the upregulation of Fas receptor expression [13,26,39]. As already mentioned, the co-existence of Fas and FasL on the surface of certain types of epithelial cells has been shown to result in suicidal or fratricide death [24,25].…”

“…Fas pathway has been previously shown to have an important role in the apoptotic cell death that is observed after treatment of various epithelial cells with IFN- [13,14,30]. Several studies have indicated that IFN-increases the sensitivity to anti-Fas mAb, likely through the upregulation of Fas receptor expression [13,26,39].…”

“…Apoptotic signaling pathways may co-operate with cytokines released by activated cytotoxic T cells, such as IFN-and TNF-, to induce tissue injuries. IFN-and/or TNF-have been shown to have various anti-proliferative influences and to induce apoptosis in neoplastic epithelial cell lines derived from various tumor tissues [13,14], including a salivary adenocarcinoma cell line [15]; however, studies addressing the effect of these cytokines in non-neoplastic epithelia are limited.…”

Progress in Understanding Autoimmune Exocrinopathy Using the Non-obese Diabetic Mouse: An Update

“…Such interactions are mediated by hormones, growth factors, cytokines delivering the signals into specific gene responses regulating cell division, apoptosis, and histodifferentiation (Jaskoll and Melnick, 1999). Specific cytokines can have multiple roles in regulating genes that encode for MMPs (Mengshol et al ., 2000), genes that are involved in programmed cell death (Gannot et al ., 1998), genes that influence neuronal responses (Soliven and Wang, 1995;Lu et al ., 1997), and genes that modulate immune responses. Potentially, one of the interesting pathways controlling this response is the insulin-like growth factor (IGF) system and its binding proteins (IGFBP), where the genes are located on mouse chromosome 1.…”

The Salivary Gland Epithelial Cell in Sjögren’s Syndrome: What Are the Steps Involved in Wounding or Killing Their Secretory Function?

“…These include the upregulation of HLA-DR due to interferon-g 3,4 , Fas and Fas ligand (FasL) induction by CD4 T cells 5,6,7,8 , as well as changes in other intracellular markers such as aquaporin 9,10,11 and costimulatory cell-surface markers 12 . The paradox of these studies is that the initial steps of apoptosis (Fas and FasL) are expressed in SS biopsies, but the actual progression to apoptosis (i.e., DNA fragmentation) in situ is a rare event in the SS biopsy 13 .…”