Inhibition of tyrosine phosphorylation prevents IFN-gamma-induced HLA-DR molecule expression.
We have previously demonstrated that HLA-DR molecule expression induced by IFN-gamma is associated with phosphatidylinositide turnover, activation of protein kinase C, and elevation of intracellular calcium. Because phosphorylation of phospholipase C-gamma 1 on tyrosine residues is known to be involved in the activation of phosphatidylinositide turnover, we investigated the role of tyrosine protein kinase (TPK) in the signal transduction for IFN-gamma-inducible DR molecule expression on T98G cells. The effects of three specific TPK inhibitors, genistein, herbimycin A, and tyrphostin, suggest that TPK is involved in the signal transduction. These inhibitors inhibited the IFN-gamma-inducible DR molecule expression in a dose-dependent manner. Being consistent with this, immunoblotting with an anti-phosphotyrosine mAb revealed that IFN-gamma induces a rapid increase in protein tyrosine phosphorylation. Genistein not only abrogated the IFN-gamma-induced enhancement of tyrosine phosphorylation, but also inhibited the IFN-gamma-induced production of inositol-4-5-triphosphate and the elevation of intracellular calcium. However, these three TPK inhibitors failed to inhibit the DR molecule expression induced by PMA and A23187. These findings suggest that the tyrosine phosphorylation is an early and critical event that precedes phosphatidylinositide turnover leading to activation of protein kinase C and elevation of intracellular calcium concentration during IFN-gamma-inducible DR molecule expression.
Ryu
K
K
Department of Microbiology and Immunology, Hamamatsu University School of Medicine, Japan.
Koide
Y
Y
Yamashita
Y
Y
Yoshida
T O
TO
D016227:Benzoquinones; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D019833:Genistein; D006684:HLA-DR Antigens / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D007529:Isoflavones / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D009570:Nitriles / Q000494:pharmacology; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011809:Quinones / Q000494:pharmacology; D011994:Recombinant Proteins; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000502:physiology
D016227:Benzoquinones; D006684:HLA-DR Antigens; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D009570:Nitriles; D011809:Quinones; D011994:Recombinant Proteins; D017828:Rifabutin; D019000:Phosphotyrosine; D000001:Calcimycin; D014443:Tyrosine; C020754:herbimycin; D007371:Interferon-gamma; D015544:Inositol 1,4,5-Trisphosphate; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D002118:Calcium