Effects of estradiol on regulation of corticotropin-releasing factor gene and interleukin-6 production via estrogen receptor type beta in hypothalamic 4B cells.

Corticotropin-releasing factor (CRF) is produced in the hypothalamic paraventricular nucleus (PVN) in response to stress and stimulates the release of adrenocorticotropic hormone in the corticotrophs. Estrogens acting centrally are able to modulate the stress responses. In fact, direct estrogenic regulation of CRF gene expression has been demonstrated in various tissues. However, the mechanisms responsible for the actions of estrogens on CRF regulation in the PVN remain undetermined. We investigated whether estradiol (E2) contributes to the regulation of CRF gene and promoter activity in hypothalamic 4B cells. Furthermore, the involvement of E2 in the regulation of interleukin (IL)-6 and its role in hypothalamic 4B cells was explored. We demonstrated the dominant expression of estrogen receptor type beta (ERbeta) and found that a physiologically relevant dose of E2 and an ERbeta agonist stimulated CRF gene transcription in hypothalamic 4B cells. E2 stimulated IL-6 transcriptional activity via ERbeta, and subsequently the levels of IL-6 mRNA and protein. We also found that treatment with IL-6 significantly reduced cell viability. Thus, these data suggest the important effects of E2 on the regulation of CRF gene and IL-6 production via ERbeta in hypothalamic 4B cells.