Modulator of intracellular Ca(2+), thapsigargin, interferes with in vitro secretion of cytokines and nitric oxide.
Interference of thapsigargin (TG), an inhibitor of endoplasmic reticulum Ca(2+) ATPase, with immune reactivity of murine macrophages was investigated under conditions in vitro. The activation of cells with lipopolysaccharide (LPS), interferon-(gamma) (IFN-(gamma)), and with acyclic nucleoside phosphonate N(6)-isobutyl-9-[2-(phosphonomethoxy)ethyl]- 2,6-diaminopurine (N(6)-isobutyl-PMEDAP) resulted in enhanced production of cytokines TNF-alpha, IL-10, chemokines RANTES/CCL5 and MIP-1alpha/CCL3, as well as in substantially augmented production of nitric oxide (NO) triggered by IFN-(gamma). The effects were in a dual mode of action influenced by TG (1 microM). While TG upregulated secretion of TNF-alpha, it inhibited secretion of IL-10 and RANTES. The immune-stimulated secretion of MIP-1alpha remained virtually unaffected, though TG on its own activated expression of MIP-1alpha in macrophages. The high-output NO production induced by IFN-(gamma), high concentrations of LPS, or by combination of IFN-(gamma) plus LPS or N(6)-isobutyl-PMEDAP was inhibited by TG. On the other hand, production of NO which was marginally activated by low concentration of LPS was upregulated by TG.
Kmonícková
Eva
E
Institute of Experimental Medicine, Academy of Sciences, Prague, Czech Republic. kmonickova@biomed.cas.cz
Canová
Nikolina Kutinová
NK
Farghali
Hassan
H
Holý
Antonín
A
Zídek
Zdenĕk
Z
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis*; D019284:Thapsigargin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016207:Cytokines; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C059499:9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; D019284:Thapsigargin; D007371:Interferon-gamma; D000252:Calcium-Transporting ATPases; D005978:Glutathione; D000225:Adenine; D002118:Calcium