Control of HLA-DR antigen expression by gamma-interferon: separate signal transduction mechanisms in malignant and nonmalignant human thyroid cells.
Three intracellular signal transduction pathways have been found to be utilized by gamma-interferon (IFN-gamma) in the induction of HLA-DR in several cell types, mainly monocytes/macrophages and B-cells: the protein kinase A (PKA); Ca(2+)-calmodulin; and protein kinase C (PKC) pathways. In this study, we investigated the role of these pathways in IFN-gamma-induced HLA-DR expression in normal and neoplastic human thyroid cells. The PKA pathway seemed to inhibit both neoplastic and normal IFN-gamma-induced HLA-DR expression; addition of thyroid-stimulating hormone to normal thyroid cells, as well as 8-bromo cyclic AMP and forskolin to normal and neoplastic cells, reduced the amount of IFN-gamma-induced HLA-DR. Moreover, H-8, a PKA inhibitor, enhanced such IFN-gamma-induced HLA-DR expression. The calcium-calmodulin pathway does not seem to play a role in IFN-gamma-induced HLA-DR expression in normal and neoplastic thyrocytes, since the Ca-ionophore A23187, EGTA, and the calmodulin antagonist, W-7, neither induced HLA-DR nor showed any effect on HLA-DR expression induced by IFN-gamma. Alone, phorbol 12-myristate 13-acetate, a PKC activator, did not induce HLA-DR on thyroid cells. However, its addition to neoplastic cells together with IFN-gamma caused a synergistic elevation of the expressed HLA-DR, whereas it significantly inhibited IFN-gamma-induced HLA-DR in normal thyrocytes. TPA had to be added before or together with IFN-gamma for optimal function. If added more than 6 h after IFN-gamma, TPA was not effective. An inactive TPA analogue did not affect HLA-DR induction, while an active analogue mimicked TPA. Staurosporine, a PKC inhibitor, reduced the TPA enhancing effect in neoplastic thyrocytes and cancelled TPA inhibition in normal cells. Moreover, when added to IFN-gamma without TPA in normal thyroid cells, staurosporine increased 3- to 4-fold the amount of HLA-DR. Thus, in normal thyroid cells the PKC pathway is activated by IFN-gamma and inhibits HLA-DR expression. In neoplastic thyrocytes, although IFN-gamma does not induce HLA-DR via PKC, this pathway augments HLA-DR expression.
Lahat
N
N
Immunology Research Unit, Carmel Hospital, Haifa, Israel.
Sobel
E
E
Kraiem
Z
Z
D000470:Alkaloids / Q000494:pharmacology; D000001:Calcimycin / Q000008:administration & dosage / Q000494:pharmacology; D002277:Carcinoma / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006042:Goiter / Q000276:immunology / Q000378:metabolism*; D006684:HLA-DR Antigens / Q000096:biosynthesis*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D007546:Isoquinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D006684:HLA-DR Antigens; D007546:Isoquinolines; D000001:Calcimycin; D007371:Interferon-gamma; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate