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Microarray Analysis of Cytokine Activation of Apoptosis Pathways in the Thyroid

Departments of Internal Medicine (S.H.W., M.V.A., Y.Y.F., J.R.B.) and Surgery (P.G.G., G.M.D.) and Comprehensive Cancer Center (R.K.), Medical School, University of Michigan Medical Center, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: James R. Baker, Jr., M.D., Department of Medicine, University of Michigan Medical School, 9240 MSRB III, Ann Arbor, Michigan 48109-0648. E-mail: jbakerjr{at}umich.edu.

It has been suggested that Fas-mediated apoptosis plays an important role in the pathogenesis of autoimmune thyroid diseases. Our previous studies have demonstrated that normal primary thyroid epithelial cells are resistant to Fas-mediated apoptosis, but the resistance can be overcome by pretreatment with a combination of interferon- (IFN-) and IL-1ß. To understand the molecular mechanism responsible for the IFN-/IL-1ß effects, we profiled changes in the transcription induced by these two cytokines in normal human thyroid cells, using cDNA microarrays. We found that IFN-/IL-1ß showed a significant increase in apoptosis-related genes such as inducible nitric oxide synthase (iNOS), receptor-interacting protein 2 (RIP2), and caspases 10. These increases were confirmed by other methods, including real-time PCR and Western blot. Furthermore, the sensitization of primary thyroid epithelial cells to Fas-mediated apoptosis by IFN-/IL-1ß was significantly blocked by a general caspase inhibitor, z-VAD, or by the combination of two specific individual caspase inhibitors. In addition, our results showed that IFN-/IL-1ß enhance p38 MAPK phosphorylation and that SB 203580, a p38 MAPK inhibitor, can inhibit IFN-/IL-1ß-induced p38 MAPK phosphorylation. SB 203580 also significantly prevented cytokine-induced iNOS expression and caspase activation and thus blocked Fas-mediated apoptosis of thyroid cells sensitized by IFN-/IL-1ß. In conclusion, our data suggest that both p38 MAPK and iNOS are involved in IFN-/IL-1ß-induced sensitization of the thyroid cells to Fas-mediated apoptosis via the activation of caspases 3, 7, and 10 and that this pathway may be further activated by BID. This hints that inflammatory cytokines regulate death-receptor-mediated apoptosis at multiple points in the process.

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