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Interleukin-1ß and Tumor Necrosis Factor (TNF)- Sensitize Human Thyroid Epithelial Cells to TNF-Related Apoptosis-Inducing Ligand-Induced Apoptosis through Increases in Procaspase-7 and Bid, and the Down-Regulation of p44/42 Mitogen-Activated Protein Kinase Activity

Center for Biologic Nanotechnology (J.R.B.) and the Departments of Medicine (E.M., S.H.W., S.U., J.D.B., J.R.B.), Physiology (L.B.), and Surgery (P.G.G., N.W.T.), University of Michigan Medical Center, Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: James R. Baker, Jr., M.D., University of Michigan Medical Center, 9220 MSRB III, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0648. E-mail: jbakerjr{at}umich.edu.

Primary thyroid cells are resistant to TNF-related apoptosis-inducing ligand (TRAIL). Previously we showed that the combination of IL-1ß and TNF facilitated TRAIL-mediated apoptosis in these cells and enhanced cell surface expression of TRAIL receptors. The aim of this study was to further characterize the mechanism by which these cytokines sensitized primary thyroid cells to TRAIL-mediated apoptosis. IL-1ß and TNF increased the concentrations of procaspase-7 and Bid. In contrast, the p44/42 MAPK (Erk) pathway was active in thyroid cells and this activity was significantly decreased after exposure to IL-1ß/TNF. A MAPK kinase inhibitor (U0126) could enhance the cytokine-induced sensitization of thyroid cells to TRAIL, reinforcing the inhibitory role of Erk on TRAIL signaling. In conclusion, IL-1ß/TNF treatment sensitizes human thyroid cells to TRAIL-mediated apoptosis through increased surface expression of TRAIL receptors, increased expression of procaspase-7 and Bid, and the inhibition of p44/42 MAPK (Erk) pathway.

This work was supported by National Institutes of Health Grants R01 A137141 and P60DK20572.

Abbreviations: cFLIP, Cellular FADD-like IL-1ß converting enzyme inhibitory protein; DcR, decoy receptor; DR, death receptor; IAP, inhibitor of apoptosis protein; IFN, interferon; MEK, MAPK kinase; NF-B, nuclear factor B; NP-40, Nonidet-P40; p90RSK, ribosomal S6 kinase; TEC, thyroid epithelial cell; TRAIL, TNF-related apoptosis-inducing ligand.

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