Activation of the cAMP pathway synergistically increases IL-1-induced IL-6 gene expression in FRTL-5 thyroid cells: involvement of AP-1 transcription factors.
Interleukin-6 (IL-6) is a multifunctional cytokine involved in autoimmune thyroid diseases such as Hashimoto's thyroiditis and Graves' disease. IL-6 is produced by infiltrating immune cells and by thyrocytes. In the latter cell type, secretion of IL-6 is stimulated notably by interleukin-1 (IL-1), thyroid-stimulating hormone (TSH) or forskolin (Fk), a cAMP elevating agent. We report here that Fk and IL-1 synergistically enhance IL-6 mRNA expression in FRTL-5 thyroid cells by mechanisms involving the cAMP/PKA pathway, and both stabilization of the IL-6 mRNA and activation of the IL-6 promoter. Point mutations or deletions of the main transcription factor binding sites in the IL-6 promoter indicated that the synergistic effect was mainly mediated by the AP-1 site, and that the CRE site contributed to this effect. The DNA binding activity of AP-1 transcription factors and the expression of c-Fos and Fra-2 proteins, were all enhanced when the cAMP and IL-1 signalling pathways were both stimulated. These findings contribute to elucidating the synergistic mechanisms that regulate IL-6 secretion by thyroid cells, and suggest that such mechanisms may be involved in the development of thyroid autoimmune disorders.
Szabo-Fresnais
Nicolas
N
INSERM U 486, Faculté de Pharmacie, F-92296 Châtenay-Malabry, France.
Blondeau
Jean-Paul
JP
Pomérance
Martine
M
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051921:Fos-Related Antigen-2 / Q000378:metabolism*; D017930:Genes, Reporter; D053583:Interleukin-1beta / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
D000067956:Adenylyl Cyclase Inhibitors; D004791:Enzyme Inhibitors; D051921:Fos-Related Antigen-2; C497874:Fosl2 protein, rat; D053583:Interleukin-1beta; D015850:Interleukin-6; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases