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Endocrinology Vol. 141, No. 6 2090-2097
Copyright © 2000 by The Endocrine Society

ARTICLES

Thyrotropin Modulates Interferon-{gamma}-Mediated Intercellular Adhesion Molecule-1 Gene Expression by Inhibiting Janus Kinase-1 and Signal Transducer and Activator of Transcription-1 Activation in Thyroid Cells1

Jongkyeong Chung, Eun Shin Park, Dohoon Kim, Jae Mi Suh, Hyo Kyun Chung, Jeonghoon Kim, Ho Kim, Soo Jung Park, O-Yu Kwon, Heung Kyu Ro and Minho Shong

Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305–701; and Departments of Internal Medicine (E.S.P., H.K., S.J.P., H.K.R., M.S.) and Anatomy (O-Y.K.), Chungnam National University, Taejon 301–040, Korea

Address all correspondence and requests for reprints to: Dr. Minho Shong, Department of Internal Medicine, Chungnam National University School of Medicine, 640 Daesadong Chungku Taejon 301–040, Korea. E-mail: minhos{at}hanbat.chungnam.ac.kr

TSH is known as an important hormone that plays the major role not only in the maintenance of normal physiology but also in the regulation of immunomodulatory gene expression in thyrocytes. The adhesion molecule intercellular adhesion molecule-1 (ICAM-1) was identified as one of the proteins that are abnormally expressed in the thyroid gland during autoimmune thyroid diseases. In this study we found that TSH inhibits interferon-{gamma} (IFN{gamma})-mediated expression of the ICAM-1 gene, and we investigated the involved mechanisms in rat FRTL-5 thyroid cells. After exposure to IFN{gamma}, ICAM-1 expression is positively regulated at the level of transcription. This effect occurs via the IFN{gamma}-activated site (GAS) element in the ICAM-1 promoter as a consequence of the activation of STAT1 (signal transducer and activator of transcription-1), but not of STAT3. On the other hand, after exposure to TSH plus IFN{gamma}, ICAM-1 transcription is negatively modulated. We found that this inhibitory effect of TSH also occurs via the GAS element. Electrophoretic mobility shift assays confirmed that the IFN{gamma}-induced DNA-binding activities of STAT1 were reduced by TSH. Furthermore, our results showed that the inhibitory effect of TSH on IFN{gamma} signaling is caused by inhibition of tyrosine phosphorylation on STAT1, Janus kinase-1 (Jak1), and IFN{gamma} receptor {alpha}, but not Jak2. In conclusion, we have identified a novel mechanism in which TSH modulates the IFN{gamma}-mediated Jak/STAT signaling pathway through the inhibition of Jak1 and STAT1.




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