Interferon-gamma induces a decrease in the intracellular calcium pump in a human salivary gland cell line.
Interferon-gamma (IFN-gamma) +/- tumor necrosis factor-alpha (TNF-alpha) induces antiproliferation and intracellular Ca2+ store depletion in a human submandibular ductal cell line (HSG), which can be reversed on cytokine removal [A. J. Wu, G. C. Chen, B. J. Baum, and I. S. Ambudkar. Am. J. Physiol. 270 (Cell Physiol. 39): C514-C521, 1996]. Here we have examined a possible mechanism for the IFN-gamma-induced intracellular Ca2+ store depletion. There was a time-dependent decrease in thapsigargin-dependent internal Ca2+ release after exposure of the cells to the cytokines. The intracellular Ca2+ pump [sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)] protein in lysates and membranes of cells treated with IFN-gamma +/- TNF-alpha, but not with TNF-alpha alone, showed 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 proliferation, since thapsigargin, 2,5-di-(t-butyl)-1,4-hydroquinone, or serum-free growth conditions induced antiproliferative effects on HSG cells without any corresponding decrease in SERCA. We suggest that the IFN-gamma-induced decrease in the level of SERCA accounts for the depleted state of internal Ca2+ stores in cytokine-treated HSG cells. These data suggest a novel mechanism for the inhibition of HSG cell growth by IFN-gamma.
Meehan
S
S
Secretory Physiology Section, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Wu
A J
AJ
Kang
E C
EC
Sakai
T
T
Ambudkar
I S
IS
D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D016895:Culture Media, Serum-Free; D003600:Cytosol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D011994:Recombinant Proteins; D013363:Submandibular Gland / Q000166:cytology / Q000201:enzymology*; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D006873:Hydroquinones; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C019359:2,5-di-tert-butylhydroquinone; D019284:Thapsigargin; D007371:Interferon-gamma; D000252:Calcium-Transporting ATPases; D002118:Calcium