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dc.contributor.authorMori, Kouki
dc.contributor.authorStone, Scott
dc.contributor.authorBraverman, Lewis E.
dc.contributor.authorDeVito, William J.
dc.date2022-08-11T08:10:02.000
dc.date.accessioned2022-08-23T16:52:54Z
dc.date.available2022-08-23T16:52:54Z
dc.date.issued1996-11-01
dc.date.submitted2008-07-09
dc.identifier.citation<p>Endocrinology. 1996 Nov;137(11):4994-9.</p>
dc.identifier.issn0013-7227 (Print)
dc.identifier.pmid8895373
dc.identifier.urihttp://hdl.handle.net/20.500.14038/42153
dc.description.abstractTumor necrosis factor-alpha (TNF alpha) is a pleiotropic cytokine that is involved in the regulation of thyroid growth and differentiated functions. The cellular and molecular mechanisms involved in mediating the effects of TNF alpha on thyroid function, however, are unknown. In a number of cell types, TNF alpha receptor binding results in the activation of specific signal transduction cascades, including protein kinase C (PKC) and the hydrolysis of sphingomyelin to ceramide. In the present study, we examined the possible role of PKC and the hydrolysis of sphingomyelin to ceramide in the regulation of TSH-induced increases in 5'-deiodinase (5'D-I) activity and 5'D-I messenger RNA (mRNA) levels in FRTL-5 cells. Further, we have recently shown that TNF alpha and interferon-gamma (IFN gamma) act synergistically to block TSH-induced increases in type I 5'D-I activity and 5'D-I gene expression in FRTL-5 rat thyroid cells. Thus, we tested the hypothesis that the activation of one or both pathways is involved in synergistic effect of TNF alpha and IFN gamma on thyroid function. In TSH-stimulated FRTL-5 cells, the addition of 12-O-tetradecanoylphorbol 13-acetate (TPA), an activator of PKC, inhibited TSH-induced increases in 5'D-I activity and 5'D-I mRNA levels in a dose-dependent manner. Incubation of FRTL-5 cells with TPA and a minimal effective concentration of IFN gamma (12.5 U/ml) in combination, however, failed to result in a synergistic inhibition of the TSH-induced increase in 5'D-I activity or 5'D-I mRNA levels. Similarly, incubation of FRTL-5 cells with sphingomyelinase (SMase), which converts sphingomyelin to ceramide, inhibited TSH-induced increases in 5'D-I activity and 5'D-I mRNA levels in a dose-dependent manner. Coincubation of FRTL-5 cells with SMase and IFN gamma failed to show a synergistic inhibition of the TSH-induced increase in 5'D-I activity or 5'D-I mRNA levels. Further, incubation of FRTL-5 cells with TPA plus SMase in the presence of IFN gamma failed to result in the synergistic inhibition of TSH-induced increases in 5'D-I activity or 5'D-I mRNA levels. The effect of TPA and SMase on TSH-induced cAMP production was examined. Low concentrations of TPA, which inhibit TSH-induced 5'D-I activity, failed to inhibit TSH-induced cAMP production or the cAMP-induced increase in 5'D-I activity. In contrast, SMase inhibited TSH-induced cAMP production in a dose-dependent manner. In the presence of IFN gamma, however, activation of either or both pathways is not sufficient to result in a synergistic inhibition of 5'D-I activity or 5'D-I gene expression. Together, our results suggest that TNF alpha-induced activation of PKC and hydrolysis of sphingomyelin can inhibit thyroid cell function. The activation of additional signal transduction pathways, however, by TNF alpha is required for the synergistic inhibition of thyroid function by TNF alpha and IFN gamma.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=8895373&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1210/en.137.11.4994
dc.subjectAnalysis of Variance
dc.subjectAnimals
dc.subjectCell Line
dc.subjectCeramides
dc.subjectCyclic AMP
dc.subject*Gene Expression Regulation, Enzymologic
dc.subjectInterferon-gamma, Recombinant
dc.subjectIodide Peroxidase
dc.subjectKinetics
dc.subjectProtein Kinase C
dc.subjectRNA, Messenger
dc.subjectRats
dc.subjectSphingomyelin Phosphodiesterase
dc.subjectSphingomyelins
dc.subjectTetradecanoylphorbol Acetate
dc.subjectThyroid Gland
dc.subjectThyrotropin
dc.subjectTranscription, Genetic
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleEffects of ceramide and protein kinase C on the regulation of type I 5'-deiodinase in FRTL-5 rat thyroid cells
dc.typeJournal Article
dc.source.journaltitleEndocrinology
dc.source.volume137
dc.source.issue11
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/526
dc.identifier.contextkey545008
html.description.abstract<p>Tumor necrosis factor-alpha (TNF alpha) is a pleiotropic cytokine that is involved in the regulation of thyroid growth and differentiated functions. The cellular and molecular mechanisms involved in mediating the effects of TNF alpha on thyroid function, however, are unknown. In a number of cell types, TNF alpha receptor binding results in the activation of specific signal transduction cascades, including protein kinase C (PKC) and the hydrolysis of sphingomyelin to ceramide. In the present study, we examined the possible role of PKC and the hydrolysis of sphingomyelin to ceramide in the regulation of TSH-induced increases in 5'-deiodinase (5'D-I) activity and 5'D-I messenger RNA (mRNA) levels in FRTL-5 cells. Further, we have recently shown that TNF alpha and interferon-gamma (IFN gamma) act synergistically to block TSH-induced increases in type I 5'D-I activity and 5'D-I gene expression in FRTL-5 rat thyroid cells. Thus, we tested the hypothesis that the activation of one or both pathways is involved in synergistic effect of TNF alpha and IFN gamma on thyroid function. In TSH-stimulated FRTL-5 cells, the addition of 12-O-tetradecanoylphorbol 13-acetate (TPA), an activator of PKC, inhibited TSH-induced increases in 5'D-I activity and 5'D-I mRNA levels in a dose-dependent manner. Incubation of FRTL-5 cells with TPA and a minimal effective concentration of IFN gamma (12.5 U/ml) in combination, however, failed to result in a synergistic inhibition of the TSH-induced increase in 5'D-I activity or 5'D-I mRNA levels. Similarly, incubation of FRTL-5 cells with sphingomyelinase (SMase), which converts sphingomyelin to ceramide, inhibited TSH-induced increases in 5'D-I activity and 5'D-I mRNA levels in a dose-dependent manner. Coincubation of FRTL-5 cells with SMase and IFN gamma failed to show a synergistic inhibition of the TSH-induced increase in 5'D-I activity or 5'D-I mRNA levels. Further, incubation of FRTL-5 cells with TPA plus SMase in the presence of IFN gamma failed to result in the synergistic inhibition of TSH-induced increases in 5'D-I activity or 5'D-I mRNA levels. The effect of TPA and SMase on TSH-induced cAMP production was examined. Low concentrations of TPA, which inhibit TSH-induced 5'D-I activity, failed to inhibit TSH-induced cAMP production or the cAMP-induced increase in 5'D-I activity. In contrast, SMase inhibited TSH-induced cAMP production in a dose-dependent manner. In the presence of IFN gamma, however, activation of either or both pathways is not sufficient to result in a synergistic inhibition of 5'D-I activity or 5'D-I gene expression. Together, our results suggest that TNF alpha-induced activation of PKC and hydrolysis of sphingomyelin can inhibit thyroid cell function. The activation of additional signal transduction pathways, however, by TNF alpha is required for the synergistic inhibition of thyroid function by TNF alpha and IFN gamma.</p>
dc.identifier.submissionpathoapubs/526
dc.contributor.departmentDivision of Endocrinology
dc.source.pages4994-9


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