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

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