title: Cooperative nongenomic and genomic actions on thyroid hormone mediated-modulation of T cell proliferation involve up-regulation of thyroid hormone receptor and inducible nitric oxide synthase expression.
abstract: Thyroid hormones (THs) exert a broad range of actions on development, growth, and cell differentiation by both genomic and nongenomic mechanisms. THs regulate lymphocyte function, but the participation of nongenomic actions is still unknown. Here the contribution of both genomic and nongenomic effects on TH-induced division of T cells was studied by using free and noncell permeable THs coupled to agarose (TH-ag). THs-ag led to cell division, but to a lesser extent than free hormones. THs induced nongenomically the rapid translocation of protein kinase C (PKC) ζ isoform to cell membranes, extracellular-signal-regulated kinases (ERK1/2) phosphorylation and nuclear factor-κB (NF-κB) activation. The signaling cascade include sphingomyelinases acting up-stream the activation of PKCζ isoform, while ERK and NF-κB are activated downstream this PKC isoenzyme. Both free and THs-ag increased the protein and mRNA levels of TH nuclear receptor TRα1, while only free hormones incremented the inducible NOS gene and protein levels as well as a calcium independent NOS activity. Both effects were blunted by PKCζ inhibition. These results indicate that THs, by triggering a nongenomic signaling cascade that involves Smases-mediated activation of PKCζ, lead to ERK 1/2 and NF-κB activation and to the genomic increase of TRs and the inducible nitric oxide synthase protein and mRNA levels, improving T lymphocyte proliferation. These finding not only contribute to the understanding of the mechanisms involved in TH modulation of lymphocyte physiology, but would also point out for the first time the interplay between genomic and nongenomic TH actions in T cells.
authors.affiliation: Centro de Estudios Farmacológicos y Botánicos, CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Barreiro Arcos
authors.forename: Helena A
authors.initials: HA
authors.lastname: Sterle
authors.forename: Maria A
authors.initials: MA
authors.lastname: Paulazo
authors.forename: Eduardo
authors.initials: E
authors.lastname: Valli
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Klecha
authors.forename: Blanca
authors.initials: B
authors.lastname: Isse
authors.forename: Claudia G
authors.initials: CG
authors.lastname: Pellizas
authors.forename: Ricardo N
authors.initials: RN
authors.lastname: Farias
authors.forename: Graciela A
authors.initials: GA
authors.lastname: Cremaschi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism*; D013974:Thyroxine / Q000378:metabolism*; D013997:Time Factors; D014284:Triiodothyronine / Q000378:metabolism*; D015854:Up-Regulation; D000099221:Protein Kinase C zeta
chemical_list: D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D013108:Sphingomyelin Phosphodiesterase; D037021:Thyroid Hormone Receptors alpha; D013974:Thyroxine; D014284:Triiodothyronine; D000099221:Protein Kinase C zeta; C496317:Nos2 protein, mouse; C535148:Mapk1 protein, mouse