Thyroid Hormone Antagonizes Tumor Necrosis Factor-α Signaling in Pituitary Cells through the Induction of Dual Specificity Phosphatase 1

摘要

Pituitary function has been shown to be regulated by an increasing number of factors, including cytokines and hormones, such as TNFα and T3. Both the proinflammatory cytokine TNFα and T3 have been suggested to be involved in the maintenance of tissue homeostasis in the anterior pituitary gland. In this report we show that T3 negatively interferes with MAPK p38 and nuclear factor-κB (NF-κB) activation by TNFα in GH4C1 cells. Our data demonstrate that MAPK p38 is specifically activated upon exposure to TNFα and that T3 abolishes this activation in a time-dependent manner by a mechanism that involves the induction of the MAPK phosphatase, DUSP1. Our data show that the pool of up-regulated DUSP1 by T3 is mainly localized to the cytosol, and that TNFα does not affect this localization. On the other hand, we show that T3 impairs the activation of the NF-κB pathway induced by TNFα, producing a significant decrease in NF-κB-dependent transcription, phosphorylation of IκBα, translocation of p65/NF-κB to the nucleus, and p65/NF-κB transactivation potential. Interestingly, the overexpression of DUSP1 inhibits the NF-κB activation achieved by either TNFα or ectopic expression of the upstream inducer of MAPK p38. Conversely, DUSP1 depletion abrogates the inhibitory effect of T3 on the induction of NF-κB-dependent transcription by TNFα. Overall, our results indicate that T3 antagonizes TNFα signaling in rat pituitary tumor cells through the induction of DUSP1.