INTERFERON-GAMMA INDUCES A DECREASE IN THE INTRACELLULAR CALCIUM-PUMPIN A HUMAN SALIVARY-GLAND CELL-LINE

Interferon-gamma (IFN-gamma) +/- tumor necrosis factor-alpha (TNF-alph a) induces antiproliferation and intracellular Ca2+ store depletion in a human submandibular ductal cell line (HSG), which can be reversed o n cytokine removal [A. J. Wu, G. C. Chen, B. J. Baum, and I. S. Ambudk ar. Am. J. Physiol. 270 (Cell Physiol. 39): C514-C521, 1996]. Here we have examined a possible mechanism for the IFN-gamma-induced intracell ular Ca2+ store depletion. There was a time-dependent decrease in thap sigargin-dependent internal Ca2+ release after exposure of the cells t o the cytokines. The intracellular Ca2+ pump [sarco(endo)plasmic retic ulum Ca2+-ATPase (SERCA)] protein in lysates and membranes of cells tr eated with IFN-gamma +/- TNF-alpha, but not with TNF-alpha alone, show ed a similar time-dependent decrease (examined using a SERCA2 antibody ). Removal of the cytokines, which resulted in recovery of cell growth and refill of internal Ca2+ stores, also increased the level of SERCA protein. The decrease in SERCA is not a result of decreased cell prol iferation, since thapsigargin, 2,5-di-(t-butyl)-1,4-hydroquinone, or s erum-free growth conditions induced antiproliferative effects on HSG c ells without any corresponding decrease in SERCA. We suggest that the IFN-gamma-induced decrease in the level of SERCA accounts for the depl eted state of internal Ca2+ stores in cytokine-treated HSG cells. Thes e data suggest a novel mechanism for the inhibition of HSG cell growth by IFN-gamma.