Thyroid hormones regulate the balance between proliferation and apoptosis of murine tumor T lymphocytes via nitric oxide synthase (NOS) and atypical protein kinase C (PKC) z modulation.

MARÍA LAURA BARREIRO ARCOS; ALICIA J KLECHA; ANA MARÍA GENARO; GRACIELA ALICIA CREMASCHI

Buenos Aires, Argentina

Congreso; XXII CONGRESO LATINOAMERICANO Y 1RO IBEROAMERICANO DE CIENCIAS FISIOLÓGICAS.; 2006

Sociedad Argentina de Fisiología

  Thyroid hormones (TH) exert a broad range of effects on development, growth and metabolism. They are able to influence proliferation and differentiation in different cell types, but their direct actions on lymphoid cells have not been elucidated. Previously we demonstrated that TH were able to stimulate proliferation and to induce division of quiescent tumor BW5147 (BW) T lymphocytes. These actions were observed up to 72 hours of culture and involved PKCz and iNOS activities. The aim of this work was to further characterize intracellular signals triggered by TH on BW lymphocyte proliferation and to analyze the actions induced by prolonged treatment with these hormones. The activation of iNOS mediated by TH was down-stream PKCz. The phosphatidylinositol 3-kinase (PI3K) blocker wortmannin was able to abrogate TH-mediated increase in proliferation and in NOS activity. Moreover, sulphasalazine, an inhibitor of NF-kB activation was also shown to impair these actions. EMSA assays showed that TH also induced NF-kB activation, effect that was blocked by the specific pseudosubstrate of PKC z. After 5 days of culture HT inhibited BW growth inducing apoptotic mechanisms as demonstrated by Hoescht staining and DNA ladder technique. These effects were accompanied by an increased in NOS activity, greater than that observed during proliferative actions of HT. Also a decreased in PKC z, while an increase in iNOS gen and protein levels were observed. These results show that proliferative HT actions are mediated by PKCz activation of iNOS, with PI3K and NF-kB acting up-stream and down-stream PKC z respectively. With prolonged HT exposition an exacerbate increase in iNOS activity would lead to PKC z decrease thus leading to apoptotic mechanisms. In conclusion HT exert opposite effects on BW lymphocyte growth, depending on the time of action and modulating iNOS and PKC z levels.