Thyroid hormone-induced stimulation of the sarcoplasmic reticulum Ca(2+) ATPase gene is inhibited by LIF and IL-6.
We investigated the effects of the leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) on 3,3', 5-triiodo-L-thyronine, or thyroid hormone (T(3))-stimulated sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) gene expression on cultured neonatal rat cardiac myocytes. A reduction of T(3) induced increases in SERCA2 mRNA levels after co-treatment with LIF or IL-6. To investigate for the molecular mechanism(s) responsible for the blunted gene expression, a 3.2-kb SERCA2 promoter construct containing a reporter gene was transfected into cardiac myocytes. T(3) treatment stimulated transcriptional activity twofold, whereas co-treatment with T(3) and either of the cytokines caused an inhibition of T(3)-induced SERCA2 transcriptional activity. A T(3)-responsive 0.6-kb SERCA2 construct also showed a similar inhibition by cytokines. Cytokine inhibition of SERCA2 transcriptional activity was also evident when a 0.6-kb SERCA2 mutant, T(3)-unresponsive promoter construct was used. Treatment with T(3) and cytokines showed a significant decrease in transcription when a reporter construct was used that was comprised of direct repeats of SERCA2 thyroid response element I. These data provide evidence for cytokine-mediated inhibitory effects on the SERCA2 promoter that may be mediated by interfering with T(3) action.
Gloss
B
B
Department of Medicine, University of California San Diego, La Jolla, California 92093-0618, USA.
Villegas
S
S
Villarreal
F J
FJ
Moriscot
A
A
Dillmann
W H
WH
D000818:Animals; D000831:Animals, Newborn; D013956:Antithyroid Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*; D013268:Stimulation, Chemical; D013963:Thyroid Hormones / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection / Q000235:genetics
D013956:Antithyroid Agents; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D012333:RNA, Messenger; D013963:Thyroid Hormones; D000252:Calcium-Transporting ATPases