Disease relevance of CRH

• These results suggest the following: (a) that the mRNA in cultured pituitary adenoma cells is qualitatively the same as that in vivo; (b) that responses of mRNA levels to CRH are time- and dose-dependent; and (c) that adenoma cells resist the inhibitory effect of dexamethasone on POMC mRNA levels and ACTH release [1].
• CRH increased and Dex decreased ACTH release and POMC mRNA levels in pituitary adenoma and bronchial carcinoid cells [2].
• Therefore, CRH and Dex tests have limited usefulness in differentiating between Cushing's disease and ectopic ACTH syndrome [2].
• The findings implicate CRH in the clinical development of acne, seborrhea, androgenetic alopecia, skin aging, xerosis, and other skin disorders associated with alterations in lipid formation of sebaceous origin [3].
• Taken together these findings suggest that CRH inhibits trophoblast invasion by decreasing the expression of CEACAM1 through CRHR1, an effect that might be involved in the pathophysiology of clinical conditions, such as preeclampsia and placenta accreta [4].

Psychiatry related information on CRH

• In the neurodegenerative disorder Alzheimer's disease (AD), levels of CRH are decreased [5].
• CRH and BEND were markedly decreased in both AD and VAD patients, and BEND levels correlated negatively with degree of dementia within the patient population [6].
• Preclinical data indicate that corticotropin-releasing hormone (CRH) has anxiogenic properties and a dysregulation in CRH systems has been suggested to play a role in a variety of stress-related psychiatric disorders, such as anxiety, depression, and eating disorders [7].
• CRH may be involved in experimentally-occurring and perhaps in naturally-occurring panic attacks as well [8].
• Moreover, acute psychological stress induces CRH-dependent mast cell degranulation [9].

High impact information on CRH

• It includes discussions on various aspects of the stress response, the hypothalamic-pituitary-adrenal and -gonadal axes, corticotropin releasing hormone, luteinizing hormone releasing hormone, interleukin-1 and -6, corticosteroids, estrogens, testosterone, dehydroepiandrosterone, growth hormone, prolactin, and thyroid hormone [10].
• Alterations in the following substances are discussed: catecholamines, acetylcholine, angiotensin II, natriuretic peptides, vasopressin, nitric oxide, serotonin, GABA, ouabain, neuropeptide Y, opioids, bradykinin, thyrotropin-releasing factor, vasoactive intestinal polypeptide, tachykinins, histamine, and corticotropin-releasing factor [11].
• Hence, cutaneous expression of the CRH/POMC system is highly organized, encoding mediators and receptors similar to the hypothalamic-pituitary-adrenal (HPA) axis [12].
• Corticotropin-releasing hormone (CRH) is a potent mediator of endocrine, autonomic, behavioural and immune responses to stress, and has been implicated in the stress-like and other aversive consequences of drug abuse, such as withdrawal from alcohol [13].
• In animals, alcohol causes activation of the sympathetic nervous system and also stimulates the release of corticotropin-releasing hormone (CRH), which has sympatho-excitatory effects when administered centrally [14].

Chemical compound and disease context of CRH

• Preeclampsia is associated with impaired regulation of the placental nitric oxide-cyclic guanosine monophosphate pathway by corticotropin-releasing hormone (CRH) and CRH-related peptides [15].
• In young normal subjects, GHRH stimulates slow-wave sleep and growth hormone secretion but inhibits cortisol release, whereas CRH has the opposite effect [16].
• These data demonstrate that in human Y-79 retinoblastoma cells, specific CRH receptors stimulate cyclic AMP formation by interacting with Gs and by affecting a Ca(2+)-inhibitable form of adenylyl cyclase [17].
• Here we have investigated the effects of CRH on another estrogen-dependent tumor cell line, human breast cancer MCF7 cells [18].
• Combined anterior pituitary function test using CRH, GRH, LH-RH, TRH and vasopressin in patients with non-functioning pituitary tumors [19].

Biological context of CRH

• The powerful effects of POMC peptides and probably CRH on the skin pigmentary, immune, and adnexal systems are consistent with stress-neutralizing activity addressed at maintaining skin integrity to restrict disruptions of internal homeostasis [12].
• AVP or angiotensin II (A-II), or their activated second messengers, also increase percentages of cells that bind CRH and store ACTH [20].
• Using RT-PCR, mRNA expression of receptors for LIF, IL-6, and CRH, and the gp130 subunit, were all detected in fetal pituitaries of 18- and 31-wk gestation [21].
• We wished to determine whether this immunoreactive substance is a product of CRH gene expression in the placenta [22].
• The transfected rat POMC promoter -706/+64, fused to the luciferase reporter gene, was induced by LIF, which exerted strong (18-fold) synergy with CRH [23].

Anatomical context of CRH

• We investigated whether locally produced CRH plays a role in trophoblast invasion, primarily by regulating CEACAM1 expression [4].
• Corticotropin-releasing hormone (CRH), which activates the hypothalamic-pituitary-adrenal axis under stress, also has proinflammatory peripheral effects possibly through mast cells [24].
• We investigated the expression of CRH receptors and the effects of CRH in the human leukemic mast cell (HMC-1) line and human umbilical cord blood-derived mast cells [24].
• To further elucidate the biologic role of CRH at peripheral sites, we examined the expression of known CRH receptor subtypes in inflamed human synovium and compared the expression patterns in normal synovium [25].
• We therefore hypothesized that activation of MAPK might mediate CRH and or/urocortin actions in the myometrium [26].

Associations of CRH with chemical compounds

• Decreased sensitivity of the glucocorticoid feedback, probably due to interaction of glucocorticoid receptors with transcription factors induced by CRH and VP, is critical for the maintenance of ACTH responses in the presence of elevated plasma glucocorticoid levels during chronic stress [27].
• Inhibition of ACTH secretion by ion channel blockers or corticosterone has potent inhibitory effects on percentages of CRH-bound cells [20].
• Cold stress for 30 min also stimulates an increase in the percentage of immunoreactive corticotropes and cells that bind CRH or arginine vasopressin (AVP) [20].
• The size of POMC mRNA did not change through the culture or after incubation with CRH or dexamethasone [1].
• Based on these findings, CRH may be an autocrine hormone for human sebocytes that exerts homeostatic lipogenic activity, whereas testosterone and growth hormone induce CRH negative feedback [3].
• Alanine substitutions of arginine 56 (R56A) and aspartic acid 62 (D62A) reduce the affinity for CRF by approximately 100-fold, while only marginally affecting the affinity for Ucn 1 [28].

Physical interactions of CRH

• Previous studies using chimeric receptors between human CRFR1 and CRFR2 have identified three potentially important regions in the second and third extracellular domains of CRF receptor for the binding of rat/human CRF [29].
• Urocortin has been found to bind with high affinity to CRF receptors [30].
• CRF-BP binds human/rat CRF and urotensin-I with high affinity, sauvagine with moderate affinity, and ovine (o) CRF with low affinity [31].
• Nuclear extracts were analyzed by electrophoretic mobility shift assay to determine NURR1 binding to the CRH promoter/enhancer [32].
• Similarly, CRH pretreatment increased the percentage of corticotropes that bound AVP [33].

Enzymatic interactions of CRH

• Plasma leptin levels were not affected by CRH infusion in either the controls or the patients despite clear-cut elevations in plasma ACTH and cortisol [34].
• We hypothesize that GRK3 upregulation may be a cellular negative feedback process directed at maximizing CRF(1) receptor desensitization by heightening GRK3 phosphorylating capacity during prolonged exposure to high CRF [35].

Regulatory relationships of CRH

• CRH-stimulated VEGF production was mediated through activation of adenylate cyclase and increased cAMP, as evidenced by the fact that the effect of CRH was mimicked by the direct adenylate cyclase activator forskolin and the cell-permeable cAMP analog 8-bromo-cAMP, whereas it was abolished by the adenylate cyclase inhibitor SQ22536 [24].
• CRF-induced increments in ACTH and cortisol were much less, but the time course was similar and peak levels attained were still higher than those in normal subjects [36].
• CRF and the non-mammalian-related peptide sauvagine bind to and activate CRF1 receptors with high affinity and equal potency [37].
• The phenotypic differentiation of locus ceruleus noradrenergic neurons mediated by brain-derived neurotrophic factor is enhanced by corticotropin releasing factor through the activation of a cAMP-dependent signaling pathway [38].
• We have studied the involvement of intracellular calcium and calcium-dependent signaling in the NPY-induced CRF release in trophoblastic cells [39].

Other interactions of CRH

• Corticotropin-releasing factor and neuropeptide Y: role in emotional integration [40].
• The recent cloning of multiple CRF receptor subtypes has precipitated a new era in CRF research that has allowed precise molecular, pharmacological and anatomical examination of mammalian CRF receptors [41].
• Abnormal signaling at corticotropin-releasing factor CRF1 and CRF2 receptors might contribute to the pathophysiology of stress-related disorders such as anxiety, depression and eating disorders, in addition to cardiac and inflammatory disorders [42].
• Multipoint linkage analysis of a candidate gene locus in rheumatoid arthritis demonstrates significant evidence of linkage and association with the corticotropin-releasing hormone genomic region [43].
• Additionally, CRH decreased CEACAM1 expression in EVTs in a dose-dependent manner [4].

Analytical, diagnostic and therapeutic context of CRH

• Furthermore the expression of CRH receptors was analyzed for the first time in pituitaries of suicide victims by in situ hybridization and quantitative PCR [44].
• CRH (10-8 M) led to a moderate increase of cortisol release (145.7 +/- 20.0%) from cortical and chromaffin adrenal cells in co-culture [45].
• We here describe the measurement of CRH-BP directly in plasma during human pregnancy using a radioimmunoassay that is not affected by the presence of the high plasma levels of CRH that occur at this time [46].
• Purification by high performance liquid chromatography (HPLC) of stromal cell culture medium revealed a major peak of CRH immunoreactivity coeluting with the standard CRH(1-41), thus indicating the secretion of the mature peptide [47].
• Using Northern blot analysis, we detected messenger RNA transcripts (2.7 kb) encoding the type-1 CRH receptor in total RNA extracted from midgestation human fetal adrenals, suggesting that the fetal adrenal cortex may be directly responsive to CRH [48].

References