Tonic glucocorticoids suppress stress-induced MKP-1 gene expression within parvocellular neurons

Mitogen-activated kinase phosophatase-1 (MKP-1) inhibits the activity of extracellular signaling regulated kinase (ERK-1/2) via dephosphorylation. ERK-1/2 has been shown to be important for membrane excitability that results in corticotropin releasing hormone (CRH) peptide secretion and has been shown to regulate CRH gene transcription. Glucocorticoid hormones produce negative feedback by suppressing both CRH secretion and CRH gene transcription, although the specific molecular mechanism is unknown. In some peripheral tissue cell types, glucocorticoids induce MKP-1 gene transcription; therefore, MKP-1 could be a target gene that contributes to some of glucocorticoid negative feedback actions. We examined whether acute stress (restraint) and tonic glucocorticoids affect MKP-1 gene transcription within the hypothalamic paraventricular nucleus (PVN) and anterior pituitary elements of the hypothalamic-pituitary-adrenal (HPA) axis and in select brain regions (prelimbic and infralimbic cortex) that provide neural input to the HPA-axis. Rats were exposed to no stress or 30 min restraint stress (RS) and were left either adrenal intact or were adrenalectomized, and MKP-1 mRNA was then measured using in situ hybridization. We found that restraint induced MKP-1 gene expression within all the brain regions examined (PVN, prelimbic cortex, and infralimbic cortex) and the pituitary. Adrenalectomy also induced MKP-1 gene expression within all the regions we examined except the prelimbic cortex. Lastly, we also found that adrenalectomy augmented stress-induced MKP-1 expression within the pituitary. These results indicate that MKP-1 gene transcription is upregulated by stress-induced activation of intracellular signal transduction pathways in the brain and pituitary. However, contrary to the previous findings in some peripheral tissues, tonic glucocorticoids suppress rather than induce stress-induced MKP-1 gene expression within the PVN.