Thyroid hormone antagonizes tumor necrosis factor-α signaling in pituitary cells through the induction of dual specificity phosphatase 1

Abstract

Pituitary function has been shown to be regulated by an increasing number of factors, including cytokines and hormones, such as TNF alpha and T-3. Both the proinflammatory cytokine TNF alpha 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-kappa B (NF-kappa B) activation by TNF alpha in GH4C1 cells. Our data demonstrate that MAPK p38 is specifically activated upon exposure to TNF alpha 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 TNF alpha does not affect this localization. On the other hand, we show that T-3 impairs the activation of the NF-kappa B pathway induced by TNF alpha, producing a significant decrease in NF-kappa B-dependent transcription, phosphorylation of I kappa B alpha, translocation of p65/NF-kappa B to the nucleus, and p65/NF-kappa B transactivation potential. Interestingly, the overexpression of DUSP1 inhibits the NF-kappa B activation achieved by either TNF alpha 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-kappa B-dependent transcription by TNF alpha. Overall, our results indicate that T-3 antagonizes TNF alpha signaling in rat pituitary tumor cells through the induction of DUSP1.