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Regulatory Mechanisms Underlying Corticotropin-Releasing Factor Gene Expression in the Hypothalamus

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Regulatory Mechanisms Underlying Corticotropin-Releasing Factor Gene Expression in the Hypothalamus Endocrine Journal 2009, 56 (3), 335-344 REVIEW Regulatory Mechanisms Underlying Corticotropin-Releasing Factor Gene Expression in the Hypothalamus KAZUNORI KAGEYAMA AND TOSHIHIRO SUDA Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan Abstract. The hypothalamic-pituitary-adrenal (HPA) axis is activated under various stressors. Corticotropin-releasing factor (CRF) plays a central role in controlling stress response, and regulating the HPA axis. CRF, produced in the hypothalamic paraventricular nucleus (PVN), stimulates adrenocorticotropic hormone (ACTH) production via CRF receptor type 1 (CRF1 receptor) from the corticotrophs of the anterior pituitary (AP). Cyclic AMP (cAMP)-protein kinase A (PKA) pathway takes a main role in stimulating CRF gene transcription. Forskolin and pituitary adenylate cyclase- activating polypeptide (PACAP) stimulate adenylate cyclase, intracellular cAMP production, and then CRF and arginine vasopressin (AVP) gene expression in hypothalamic 4B cells. Interleukin (IL)-6, produced in the PVN, both directly and indirectly stimulates CRF and AVP gene expression. Estradiol may enhance the activation of CRF gene expression in response to stress. The HPA axis is regulated by a negative feedback mechanism, because glucocorticoids inhibit both CRF production in the hypothalamic PVN and ACTH production in the pituitary. Hypothalamic parvocellular neurons in the PVN are known to express glucocorticoid receptors, and glucocorticoids are able to regulate CRF gene transcription and expression levels directly in the PVN. Glucocorticoids-dependent repression of cAMP-stimulated CRF promoter activity is mainly localized to promoter sequences between –278 and –233 bp. Both negative glucocorticoid regulatory element (nGRE) and serum response element (SRE) are involved in the repression of the CRF gene in the hypothalamic cells. Key words: Corticotropin-releasing factor, Hypothalamus, Stress, Cyclic AMP, Receptor (Endocrine Journal 56: 335-344, 2009) THE HYPOTHALAMIC-PITUItaRY-ADRENAL Stimulation of CRF gene in the hypothalamus (HPA) axis is activated under various stressors [1]. Corticotropin-releasing factor (CRF) plays a central Involvement of cAMP on CRF gene transcription role in controlling stress response, and regulating the HPA axis. CRF, produced in the hypothalamic paraven- Cyclic AMP (cAMP)-protein kinase A (PKA) path- tricular nucleus (PVN), stimulates adrenocorticotropic way takes a main role in stimulating CRF synthesis hormone (ACTH) production via CRF receptor type 1 [3-5]. There are several candidates for activating CRF (CRF1 receptor) from the corticotrophs of the anterior neurons. For example, pituitary adenylate cyclase-ac- pituitary (AP). ACTH then stimulates glucocorticoid tivating polypeptide (PACAP), a member of the secre- release from the adrenal glands [2]. Glucocorticoid in tin/glucagon/vasoactive intestinal peptide (VIP) fam- turn inhibits both CRF production in the hypothalamic ily, is one of the putative hormones. Both PACAP and PVN and ACTH production in the pituitary. the PACAP-selective PACAP receptor type 1 (PAC1 receptor) are known to be highly expressed in the hy- pothalamus, including the parvocellular and magno- cellular subdivisions of the PVN, and the supraoptic Received: March 9, 2009 nucleus (SON) [6, 7]. PACAP has shown to stimu- Accepted: March 11, 2009 late cAMP production in the AP [8]. PACAP also in- Correspondence to: Kazunori KAGEYAMA, M.D., Ph.D., Department of Endocrinology and Metabolism, Hirosaki creases CRF mRNA levels in the parvocellular region University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, of the PVN, suggesting that PACAP is involved in the Aomori 036-8562, Japan positive regulation of CRF gene expression [9]. 336 KAGEYAMA et al. 1000 Computer analysis of the proximal CRF promot- ** er reveals several possible binding sites for transcrip- ** ** tional factors, such as cAMP-response element (CRE), 800 activator protein 1 (AP-1) protein (Fos/Jun) binding n sites, half glucocorticoid regulatory element (GRE), ) and half estrogen-responsive element (ERE) [10]. 600 Forskolin or PACAP stimulates adenylate cyclase, ** ** and then increases intracellular cAMP levels in hypo- (% of control 400 thalamic 4B cells (Fig. 1) [11]. Forskolin increases cAMP productio CRF transcriptional activity in the hypothalamic cells (Fig. 2), which corresponds with previous studies us- 200 * ing other cells [4, 5, 12]. The forskolin-stimulated ac- tivity of CRF gene transcription is reduced in 4B cells 0 transfected with a mutant construct, CRF-233Mtluc, C 0.01 0.1 1101 10 100 1000 in which the CRE element (TGACGTCA) is mutat- Fsk (µM) PACAP (nM) ed (TGGATCCA), or a deletion mutant construct of Fig. 1. Effects of PACAP on cAMP production in 4B cells. the CRF gene promoter, CRF-220luc (Fig. 3) [13]. *P < 0.05, **P < 0.005 (compared with control (C)). Cells Therefore, the forskolin-induced CRF gene transcrip- were pre-incubated for 20 min with medium containing tion is mainly mediated by CRE, which includes -220 0.1 mM 3-isobutyl-1-methylxanthine, followed by to –233 bp, on the CRF 5’-promoter region in hypo- the addition of forskolin (Fsk) or PACAP. The level thalamic cells. of intracellular cAMP was measured by cAMP EIA. The PKA pathway is mainly involved in CRF gene (Reproduction from Ref. [11] with permission of the publisher.) Copyright 2007, Society for Endocrinology. regulation in the hypothalamic cells, because a PKA inhibitor strongly blocks the forskolin-induced CRF promoter activity [14]. This result supports our previ- ous report on the involvement of the PKA pathway in sion via the cAMP-PKA pathway in hypothalamic CRF synthesis and release in hypothalamic explants 4B cells (Fig. 4). PACAP is detected in nerve termi- [3]. Activation of the PKA pathway leads to binding nals that innervate AVP-containing neurons in the rat of CRE-binding protein (CREB) to the CRE on the hypothalamus [18], and its receptor mRNA is highly CRF promoter in hypothalamic cells as well as in hu- expressed in AVP-containing neurons [18]. The 4B man placental cells [15]. Protein kinase C (PKC) and cells also express PAC1 and VIP-preferring receptors p38 mitogen-activated protein (MAP) kinase are also (VPAC receptors). Therefore, activation of PAC1 or involved in the regulation of the forskolin-induced VPAC receptors by PACAP induces production of in- CRF gene expression, because both SB203580, an in- tracellular cAMP, activating the transcription of AVP hibitor highly specific for p38 kinase, and bisindo- gene in hypothalamic cells. Taken together, PACAP- lylmaleimide I (BIM), a PKC inhibitor, suppress for- induced intracellular cAMP production is involved skolin-induced CRF promoter activity [14]. At the in stimulating the transcription of both CRF and AVP same time, PD98059, a selective MAP kinase kinase genes via the PKA pathway in the hypothalamic cells. (MEK)-extracellular signal-related kinases (ERK) in- hibitor, and SP600125, a Jun amino-terminal kinas- Involvement of IL-6 on CRF gene transcription es (JNK) 1/2/3 inhibitor, does not show inhibitory ef- fects. Therefore, PKA, PKC, and p38 MAP kinase Interleukin (IL)-6 shows a variety of biological ac- pathways are involved in forskolin-induced activation tivities. Plasma IL-6 levels rise in response to both of CRF gene transcription in hypothalamic 4B cells. immune activation and non-immune stress [19, 20]. PACAP regulates the HPA axis by stimulation of IL-6 prompts lymphocytic proliferation and differ- CRF gene expression in the hypothalamus (Fig. 4) and entiation [21] and induces production of acute-phase through direct effects on pituitary corticotrophs [14, proteins in the liver [22]. In addition, IL-6 stimulates 16, 17]. PACAP also stimulates both arginine vaso- the HPA axis [23], resulting in increasing glucocorti- pressin (AVP) gene transcription and mRNA expres- coid levels, which in turn suppress IL-6 production [24, REGULATION OF CRF IN THE HYPOTHALAMUS 337 2000 2000 * * 1500 1500 ) ) 1000 1000 (% of control (% of control CRF 5’-Promoter Activity CRF 5’-Promoter Activity 500 500 0 0 0612 18 24 C 0.01 0.1 110 Time (h) Fsk (µM) Fig. 2. Effects of forskolin on CRF 5’-promoter activity in 4B cells. Control cells treated with medium alone are indicated as (C). *P < 0.05 (compared with control [C]). Time-dependent changes in forskolin-induced CRF 5’-promoter activity (left panel). Cells were incubated with medium containing 10mM forskolin. Dose-dependent changes in forskolin-induced CRF 5’-promoter activity (right panel). Cells were incubated for 2 h with medium containing 0.01 to 10mM forskolin (Fsk). (Reproduction from Ref. [13] with permission of the publisher.) Copyright 2008, Editrice Kurtis srl. -907 -233 -220 0+170 Control PACAP (2 h) PACAP (6 h) PACAP (24 h) (A) CRF Promoter CRE CRF (B) 2000 AVP 1500 B2MG ) + 300 * CRF 1000 + ** * AVP (% of control ) 200 * * CRF 5’-Promoter Activity 500 ** mRNA ** * (% of control 0 100 C Fsk C Fsk C Fsk C Fsk CRF-907luc CRF-233 luc CRF-233 Mt luc CRF-220 luc 0 Fig. 3. Effects of CRE deletion on forskolin-induced CRF 0 6 12 18 24 Time (h) 5’-promoter activity in 4B cells. (A) Schematic representation of CRE in the CRF promoter. (B) Fig. 4. Effects of PACAP on CRF and AVP mRNA levels. 4B Cells were transfected with full-length (CRF-907luc), Cells were stimulated with 100 nM PACAP for 2, 6, deleted (CRF-220luc or CRF-233luc), or mutant (CRF- and 24 h. Expression of CRF and AVP mRNA was 233Mtluc) promoter constructs, and then incubated for examined by RT-PCR. *P < 0.05, **P < 0.005 (compared 2h with 10mM forskolin alone (Fsk) or vehicle (C). *P with control). (Reproduction from Ref. [11] with < 0.05 (compared with forskolin alone [Fsk] in CRF- permission of the publisher.) Copyright 2007, Society 907luc transfected cells). +P < 0.05 (compared with each for Endocrinology. control). (Reproduction from Ref. [13] with permission of the publisher.) Copyright 2008, Editrice Kurtis srl. 338 KAGEYAMA et al. 800 M4BHypo AP C1 C2 C3 ** ERα 600 ** ) ** ++ ERβ 400 * (% of control # B2MG CRF 5’ Promoter Activity 200 Fig.
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