Cytokines induce NF-κB, Nurr1 and corticotropin-releasing factor gene transcription in hypothalamic 4B cells.

ABSTRACT

OBJECTIVE: In the hypothalamus, corticotropin-releasing factor (CRF) plays a central role in regulating stress responses. Cytokines are important mediators of the interaction between the neuroendocrine and immune systems, and are implicated in the regulation of CRF expression. Following inflammatory challenges, interleukin (IL)-1 or IL-6 stimulates the hypothalamic-pituitary-adrenal axis. CRF promoter contains multiple nuclear factor (NF)-kappaB and Nurr1 binding sites. In the present study, we determined the ability of the signaling pathways to activate the CRF gene in the hypothalamic paraventricular nucleus following inflammatory challenge. METHODS: Cytokine-induced changes in CRF gene expression were examined in the hypothalamic system. Luciferase assay and Western blotting were performed to assess transcriptional activity and the nuclear translocation of transcriptional factors. RESULTS: IL-1beta, IL-6 and tumor necrosis factor (TNF)-alpha stimulated the nuclear expression levels of NF-kappaB, NF-kappaB-dependent Nurr1 and c-Fos proteins. Direct stimulatory effects of TNF-alpha and IL-1beta, in addition to IL-6, were found on the transcriptional activity of the CRF gene in hypothalamic 4B cells. CONCLUSION: These cytokines are involved in the regulation of CRF gene activity in hypothalamic cells.