Tyrosine phosphorylation pathway is involved in interferon-gamma (IFN-gamma) production; effect of sodium ortho vanadate.
The molecular mechanisms regulating IFN-gamma production have yet to be well characterized. We describe here how treatment of activated cultures of peripheral blood mononuclear cells (PBMC) with the phosphotyrosine phosphatases (PTP) inhibitor sodium ortho vanadate results in greatly enhanced IFN-gamma production. Conversely, cellular proliferation of the same cultures is profoundly inhibited by treatment with vanadate, while the expression of IL-2R and DR molecules on activated lymphocytes remains substantially unmodified. Increased IFN-gamma production, but not inhibition of cellular proliferation, was also observed in mitogen-activated vanadate-treated Jurkat cells. On the other hand, IFN-gamma production induced in cultures of PBMC treated or not with vanadate, was strongly inhibited by incubation with the protein tyrosine kinase (PTK) inhibitor herbimycin A. As a result of the inhibited phosphatase activity, substrates for PTK become hyperphosphorylated on tyrosine residues, as shown by Western blot analysis of cell lysates from cultures of PBMC treated with vanadate. We suggest that the tyrosine phosphorylation pathway plays a role in regulating IFN-gamma production.
Giovannetti
A
A
Department of Clinical Immunology and Allergy, La Sapienza University of Rome, Italy.
Aiuti
A
A
Pizzoli
P M
PM
Pierdominici
M
M
Agostini
E
E
Oliva
A
A
Dianzani
F
F
Aiuti
F
F
Pandolfi
F
F
D002455:Cell Division / Q000187:drug effects; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism*; D019000:Phosphotyrosine; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology*
D006684:HLA-DR Antigens; D010750:Phosphoproteins; D015375:Receptors, Interleukin-2; D019000:Phosphotyrosine; D014638:Vanadates; D014443:Tyrosine; D007371:Interferon-gamma