EFFECT OF TUMOR-NECROSIS-FACTOR-ALPHA AND INTERFERON-GAMMA ON THE GROWTH OF A HUMAN SALIVARY-GLAND CELL-LINE

Interferon-gamma (IFN-gamma) is a product of activated T-lymphocytes, and tumor necrosis factor-alpha (TNF-alpha) is a product of both lymphocytes and macrophages. These cell types are often present at sites of tissue damage secondary to chronic infection or autoimmune disease. The purpose of this study was to characterize the effects of TNF-alpha and IFN-gamma on a human submandibular gland epithelial cell line (HSG). IFN-gamma caused a concentration-dependent decrease in HSG cell growth (similar to-70% in 6 days). Conversely, TNF-alpha alone had little effect on the growth of these cells. When these cytokines were added in combination (20 units/ml TNF-alpha and 1,000 units/ml of IFN-gamma), there was a synergistic antiproliferative effect; no apparent cell growth was observed. The cytokine-induced antiproliferative effect was reversible. After the apparent cessation of cell growth for 3-6 days, removal of the cytokines permitted complete growth recovery. Further, cells that recovered and exhibited growth patterns that were similar to control cells remained susceptible to the antiproliferative effects of the cytokines. Flow cytometry revealed that the percentage of cells in G0/G1 with the combination of cytokines was significantly increased by 24 h. The antiproliferative effect of IFN-gamma alone and that of IFN-gamma and TNF-alpha in combination were blocked completely using an antibody to the IFN-gamma receptor. A hypothesized mechanism of tissue damage in autoimmune inflammatory disorders is via up-regulation of cell surface markers such as intercellular adhesion molecule type I (ICAM-1) and histocompatibility antigen HLA-DR which can exacerbate the inflammatory process. Treatment of HSG cells with IFN-gamma, with or without TNF-alpha, resulted in increased levels of ICAM-1 and the acquisition of HLA-DR expression. These aggregate data suggest that IFN-gamma alone can regulate the expression of cell surface markers involved in the inflammatory process as well as cause a potent yet reversible inhibition of HSG cell growth that is modulated by the presence of TNF-alpha. (C) 1994 Wiley-Liss, Inc.