Disease relevance of Crh

• Corticotropin-releasing factor stimulates phospholipid methylation and corticotropin secretion in mouse pituitary tumor cells [1].
• Corticotropin-releasing hormone (CRH) requirement in Clostridium difficile toxin A-mediated intestinal inflammation [2].
• In addition, the authors examine a potential role for CRH in inflammatory injury after stroke by identifying functional CRH receptors on astrocytes and microglia, which are cells that are known to be involved in brain inflammation [3].
• Intracerebroventricular injection of CRF or urocortin (Ucn) reduces appetite and body weight [4].
• Lastly, exposure of tail explants to hypoxia increased CRF and urocortin 1 but strongly decreased CRF-BP mRNA expression [5].

Psychiatry related information on Crh

• The corticotropin-releasing factor (CRF) system has been hypothesized to mediate the motivational effects of drug dependence [6].
• This study reveals a cardinal role for CRF/CRF1 receptor pathways in the negative affective states of opiate withdrawal and suggests therapeutic strategies for the treatment of opiate addiction [6].
• Corticotropin-releasing factor (CRF) systems are involved in locomotor and feeding behaviors [7].
• The view that CRH hypersecretion underlies anxiety and mood disorders was recently supported by preclinical and clinical data obtained after application of the CRH receptor (CRH-R1) antagonist NBI30775 (R121919) [8].
• It has also been hypothesized that, during postnatal development of the stress system, CRH controls the activity of the HPA axis and mediates the effects of early disturbances, e.g. 24 h of maternal deprivation [9].

High impact information on Crh

• Urocortin is a member of the corticotropin-releasing hormone peptide family and is found in many discrete brain regions [10].
• In response to stress, Crh released from the paraventricular nucleus (PVN) of the hypothalamus activates Crh receptors on anterior pituitary corticotropes, resulting in release of adrenocorticotropic hormone (Acth) into the bloodstream [11].
• While both hormones increased expression of hypothalamic corticotropin-releasing hormone (CRH), ADP had no substantial effect on other neuropeptide targets of leptin [12].
• Corticotropin-releasing hormone (CRH), a 41-amino-acid neuropeptide produced in the paraventricular nucleus of the hypothalamus and many regions of the cerebral cortex, has been implicated in both the HPA axis and behavioural responses to stress [13].
• To define the importance of CRH in the response of the HPA axis to stress and fetal development, we have constructed a mammalian model of CRH deficiency by targeted mutation in embryonic stem (ES) cells [13].

Chemical compound and disease context of Crh

• The relative contribution of IL-6 in stimulating CRF expression in the PVN and neural activity throughout the brain during endotoxemia was also investigated in IL-6-deficient mice after an ip injection of LPS [14].
• Hypovolemia produced by retro-orbital bleeding also significantly elevated corticosterone in CRH KO mice [15].
• Corticotropin-releasing factor-induced adrenocorticotropin hormone release and synthesis is blocked by incorporation of the inhibitor of cyclic AMP-dependent protein kinase into anterior pituitary tumor cells by liposomes [16].
• Identification of a corticotropin-releasing factor-binding protein in the plasma membrane of AtT-20 mouse pituitary tumor cells and its regulation by dexamethasone [17].
• To further examine the correspondence between autoimmune disease and chronic stress, we asked whether the brains of autoimmune mice show a shift in the corticotropin-releasing factor (CRF) to vasopressin (AVP) ratio [18].

Biological context of Crh

• Our findings suggest that during inflammation, IL-6 most likely compensates for the effects of CRH deficiency on food intake [19].
• However, CRH and vasopressin (AVP) mRNA levels in the transgenic mice are increased by 82 and 35%, respectively, to compensate for the excess CRH-BP, consistent with the idea that CRH-BP levels are important for homeostasis [20].
• The data show that long-term GR dysfunction can be associated with reduced activity of CRH neurons in the PVN and decreased sensitivity of pituitary CRH-R1 mRNA to stimulus-induced downregulation [21].
• Corticotropin-releasing hormone is a main regulator of mammalian stress response by stimulating pituitary proopiomelanocortin (POMC) gene expression, and thus adrenocorticotropic hormone (ACTH) secretion, which then causes glucocorticoid release from the adrenal [22].
• After treatment with CRH, intracellular POMC-luciferase activity was significantly higher from the stimulation observed with transfection of the parental POMC-luciferase construct [22].

Anatomical context of Crh

• These findings, along with the regulation of IL-6 by CRH, support the importance of the interaction between the immune system and the HPA axis in the pathophysiology of inflammatory diseases [19].
• As shown by immunohistochemistry and confocal microscopy analysis, CRH administration increased p-ERK1/2 levels specifically in the CA3 and CA1 hippocampal subfields and basolateral complex of the amygdala, both structures related to external environmental information processing and behavioral aspects of stress [23].
• Here we demonstrate that, compared with wild type, mice genetically deficient in CRH (Crh(-/-)) have dramatically reduced ileal fluid secretion, epithelial cell damage, and neutrophil transmigration 4 h after intraluminal toxin A administration [2].
• The mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2) mediates several functions in different forebrain structures and recently has been implicated in CRH signaling in cultured cells [23].
• Corticotropin-releasing factor and the urocortins induce the expression of TLR4 in macrophages via activation of the transcription factors PU.1 and AP-1 [24].

Associations of Crh with chemical compounds

• In contrast, toxin A administration in Crh(-/-) mice fails to result in an increased SP content [2].
• We demonstrate that during inflammation CRH is required for a normal adrenocorticotropin hormone (ACTH) increase but not for adrenal corticosterone rise [19].
• These CRF-stimulated effects were also blocked by the glucocorticoid dexamethasone [1].
• CRF-induced increases in phospholipid methylation and ACTH secretion were reduced when cells were treated with the phospholipid methyltransferase inhibitors 3-deazaadenosine and L-homocysteine thiolactone [1].
• The methionine sulfoxide derivative of CRF was less potent than CRF was in stimulating both phospholipid methylation and hormone secretion, and the COOH-terminal free acid analogue of CRF had no effect on either process [1].

Physical interactions of Crh

• Although DEX treatment of AtT-20 cells did not affect AP-1 DNA binding capacity of nuclear extracts, DEX pretreatment blunted the stimulation of AP-1 binding in response to CRF [25].
• Further, CRF has been shown to contribute to excitability of hippocampal neurons during embryonic development by binding to CRF-R1; depolarization induced excitability appears to be critical for cell survival [26].
• CRH and PKA rapidly increase nuclear DNA binding activity of NGFI-B dimers but not monomers [27].

Co-localisations of Crh

• The activity of the PVN CRF cells was estimated from the number of PVN cells colocalizing CRF mRNA and the protein Fos [28].

Regulatory relationships of Crh

• Modulation of urocortin-induced hypophagia and weight loss by corticotropin-releasing factor receptor 1 deficiency in mice [4].
• In the paraventricular nucleus, Cam-CRHR1 animals displayed enhanced CRH and decreased vasopressin expression levels [9].
• Leptin rapidly inhibits hypothalamic neuropeptide Y secretion and stimulates corticotropin-releasing hormone secretion in adrenalectomized mice [29].
• Corticotropin-releasing hormone stimulates the expression of the steroidogenic acute regulatory protein in MA-10 mouse cells [30].
• Leptin and corticosterone downregulated CRH expression in the paraventricular hypothalamic nucleus (PVH) [31].

Other interactions of Crh

• However, host resistance to the infection was retained in CRF- or Ucn-treated mice [32].
• Avp also potentiates the actions of CRH (Crh) and appears to be an important mediator of the hypothalamic-pituitary-adrenal axis response to chronic stress [33].
• Corticotropin-releasing factor (CRF) receptor type 2beta (CRFR2beta) is expressed in the heart [34].
• Severity of the catabolic condition differentially modulates hypothalamic expression of growth hormone-releasing hormone in the fasted mouse: potential role of neuropeptide y and corticotropin-releasing hormone [35].
• Urocortin-II and urocortin-III are cardioprotective against ischemia reperfusion injury: an essential endogenous cardioprotective role for corticotropin releasing factor receptor type 2 in the murine heart [34].

Analytical, diagnostic and therapeutic context of Crh

• 125I-CRH binding autoradiography revealed no differences between WT and TG animals in any of the brain regions that were studied [21].
• In agreement with a previous report, CRH inhibited the constitutive NF-kappaB DNA-binding activity in AtT20 cells, as shown by electrophoretic mobility-shift assay, as soon as within 15 min of treatment [22].
• Animal models of CRH excess and CRH receptor deficiency display altered adaptations to stress [36].
• Combined immunohistochemistry and in situ hybridization revealed that CRFR-1-ir was most frequently colocalized to CRF in mouse PVN, whereas only a small percentage of oxytocin and vasopressin-producing cells coexpressed CRFR-1-ir [37].
• In whole-cell recordings, both CRF and ethanol enhanced gamma-aminobutyric acid-mediated (GABAergic) neurotransmission in CeA neurons from wild-type and CRF2 receptor knockout mice, but not CRF1 receptor knockout mice [38].

References