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 T_(3). Both the proinflammatory cytokine TNFα and T_(3) have been suggested to be involved in the maintenance of tissue homeostasis in the anterior pituitary gland. In this report we show that T_(3) 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 T_(3) 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 T_(3) is mainly localized to the cytosol, and that TNFα does not affect this localization. On the other hand, we show that T_(3) 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 T_(3) on the induction of NF-κB-dependent transcription by TNFα. Overall, our results indicate that T_(3) antagonizes TNFα signaling in rat pituitary tumor cells through the induction of DUSP1.