Induction of transcription factor interferon regulatory factor-1 by interferon-? (IFN?) and tumor necrosis factor-? (TNF?) in FRTL-5 cells

Abstract

While it is well known that interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF alpha) play a role in the regulation of thyroid growth and differentiated functions, the cellular and molecular mechanisms involved in mediating the effects of IFN gamma and TNF alpha on thyroid function are unknown. In the present study, we used FRTL-5 rat thyroid cells to examine the effects of IFN gamma and TNF alpha on gene expression of transcription factor interferon regulatory factor-1 (IRF-1), which is involved in mediating the effects of these cytokines in a number of cell types. Northern blot analysis of FRTL-5 mRNA showed a single IRF-1 mRNA at 2.2 Kb. In quiescent FRTL-5 cells, IRF-1 mRNA levels were low but detectable by Northern analysis. Incubation of FRTL-5 cells with IFN gamma or TNF alpha resulted in a dose- and time-dependent increase in IRF-1 mRNA levels. We have shown that TNF-alpha and IFN-gamma act synergistically to block the TSH-induced increase in type I 5'-deiodinase(5'D-I) activity and 5'D-I gene expression in FRTL-5 rat thyroid cells. Incubation of FRTL-5 cells with IFN gamma and TNF alpha in combination, however, did not synergistically increase IRF-1 mRNA levels. Electrophoretic mobility shift assay (EMSA) revealed that IFN gamma induced the formation of a single complex to a IFN gamma activation site (GAS) probe in a dose dependent manner. Several lines of evidence suggest that TNF alpha activates transcription factor nuclear factor-kappa B (NF kappa B) through activation of protein kinase C (PKC) or the hydrolysis of sphingomyelin to ceramide in a number of cell types. Here we demonstrate that hydrolysis of sphingomyelin to ceramide by sphingomyelinase (SMase), but not activation of PKC by 12-O-tetradecanoylphorbol 13-acetate (TPA), was involved in the activation of NF kappa B in FRTL-5 cells. Similarly, hydrolysis of sphingomyelin to ceramide, but not activation of PKC, resulted in an increased in IRF-1 mRNA levels in FRTL-5 cells. The present data demonstrate that IFN gamma and TNF alpha increase IRF-1 mRNA levels in FRTL-5 cells through activation of GAS and NF kappa B binding proteins, respectively. Thus, our results suggest that upregulation of IRF-1 may play a role in mediating the effects of IFN gamma and TNF alpha on thyroid function. Our results also suggest that the induction of IRF-1 mRNA by IFN gamma and TNF alpha is not the cellular mechanism involved in the synergistic effect of these cytokines on thyroid function.

Intratumoral interferon regulatory factor (IRF)‐1 but not IRF‐2 is of relevance in predicting patient outcome in ovarian cancer

“…The lack of a significant association between intratumoral IRF-2 and IFN-g in the examined ovarian cancer samples as well as the fact that IRF-1 and IFN-g were found to be independent of each other in predicting overall survival may substantiate our in vitro-findings and those of others 23,24 showing that the expression of both IRFs is not exclusively regulated by IFN-g, but may be significantly influenced by other locally acting cytokines such as IL-1 and TNF-a, but also by growth factors like EGF. In this context, it should be emphasized that especially IRF-1, as a relevant prognosticator, should not be regarded as a simple secondmessenger of IFN-g, but as a variable that reflects local anti-tumor immune response and other events influencing tumor growth, namely more precisely than does IFN-g.…”

Lysophosphatidic Acid Inhibits CC Chemokine Ligand 5/RANTES Production by Blocking IRF-1–Mediated Gene Transcription in Human Bronchial Epithelial Cells

“…IRF-1 is induced by a number of stimuli, including IFN-g, TNFa, and LPS, in a variety of cells (37)(38)(39) and is supposed to be an essential transcriptional activator for IFN-g-induced CCL5/ RANTES expression in murine macrophages (40,41). Consistent with previous reports (9,42), costimulation with IFN-g and TNF-a induced CCL5/RANTES production in BEAS-2B cells and was associated with IRF-1 expression (Fig.…”

Prevention of lymphocytic thyroiditis in iodide-treated non-obese diabetic mice lacking interferon regulatory factor-1

“…In fact, targeted disruption of the IRF-1 gene in mice results in reduced incidence and severity of collagen-induced arthritis (19). Recently, we have shown that IFNg induced IRF-1 gene expression in FRTL-5 rat thyroid cells (20). Taken together, IRF-1 may play a role in the pathogenesis of AITD.…”