BACKGROUND: Natural killer (NK) cells are CD3 (-) CD14 (-) CD56 (+) lymphocytes. They play an important role in the body's innate immune response. They can induce spontaneous killing of cancer cells or virus-infected cells via the Fas/Fas ligand or the granzyme/perforin systems. The corticotropin-releasing hormone (CRH) is an important regulator for the body's stress response. It promotes proliferation and migration of various cancer cells through the CRH type 1 receptor under stress, and also inhibits NK or T cell activity. However, the relationship of CRH and NK cell migration to the target has not been confirmed. Herein, we study the effect of CRH on NK cell migration. METHODS: We used the human NK cell line, NK-92MI, and tested the expression of CRH receptor type 1 on NK-92MI by RT-PCR. This was to examine the effect of CRH on tumor and NK cell migration, thus NK cells (NK-92MI) were incubated with or without CRH and then each CRH treated cell's migration ability compared to that of the CRH untreated group. RESULTS: We confirmed that CRH receptor type 1 is expressed in NK-92MI. CRH can decrease NK cell migration in a time-/dose-dependent manner. CONCLUSION: These data suggest CRH can inhibit NK cell migration to target cells.
Cell Movement* ; Corticotropin-Releasing Hormone* ; Homicide ; Humans* ; Immunity, Innate ; Killer Cells, Natural* ; Lymphocytes ; Receptors, Corticotropin-Releasing Hormone

OBJECTIVES: Corticotropin releasing factor (CRF) plays a primary role in coordinating the neuroendocrine, autonomic, immune and behavioral responses to stress. CRF exerts its action through two major receptors, corticotropin-releasing factor 1 Receptor (CRF-R1) and corticotropin-releasing factor 2 receptor (CRF-R2). Using two types of chronic stress models, we investigated the changes of CRF-R1 mRNA and CRF-R2A mRNA expressions and CRF mRNA in the stress related brain circuit areas. METHODS: Male Sprague-Dawley rats were exposed to either immobilization stress or variable intermittent unpredictable stress for 10 days and then in situ hybridization histochemistry was used to quantify CRF expression in the brain. RESULTS: 1) CRF1 receptor mRNA expressions were decreased in bed nucleus stria terminalis (BNST) following stressors. 2) CRF2A receptor mRNA expressions were increased in lateral septum following stressors. 3) CRF mRNA expressions were increased in central nucleus of amygdala (CeA) and BNST. CONCLUSION: The increased CRF mRNA of CeA and BNST may be related with anxiety response in the repeated stress. Down-regulation of CRF-R1 mRNA expression in BNST may represent a compensatory adaptation to chronic stress and may be involved in the anxiety response, whereas up-regulation of CRF-R2A mRNA expression in lateral septum may represent an anxiety response or impaired learning but the functional meaning is uncertain.
Adrenocorticotropic Hormone* ; Amygdala ; Anxiety ; Brain ; Corticotropin-Releasing Hormone* ; Down-Regulation ; Humans ; Immobilization ; In Situ Hybridization ; Learning ; Male ; Rats, Sprague-Dawley ; Receptors, Corticotropin-Releasing Hormone ; RNA, Messenger ; Up-Regulation

Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are common gastrointestinal (GI) diseases; however, there is frequent overlap between FD and IBS patients. Emerging evidence links the activation of corticotropin releasing factor (CRF) receptors with stress-related alterations of gastric and colonic motor function. Therefore, we investigated the effect of peripheral CRF peptide and water avoidance stress (WAS) on upper and lower GI transit in guinea pigs. Dosages 1, 3, and 10 µg/kg of CRF were injected intraperitoneally (IP) in fasted guinea pigs 30 minutes prior to the intragastric administration of charcoal mix to measure upper GI transit. Colonic transits in non-fasted guinea pigs were assessed by fecal pellet output assay after above IP CRF doses. Blockade of CRF receptors by Astressin, and its effect on GI transit was also analyzed. Guinea pigs were subjected to WAS to measure gastrocolonic transit in different sets of experiments. Dose 10 µg/kg of CRF significantly inhibited upper GI transit. In contrast, there was dose dependent acceleration of the colonic transit. Remarkably, pretreatment of astressin significantly reverses the effect of CRF peptide on GI transit. WAS significantly increase colonic transit, but failed to accelerate upper GI transit. Peripheral CRF peptide significantly suppressed upper GI transit and accelerated colon transit, while central CRF involved WAS stimulated only colonic transit. Therefore, peripheral CRF could be utilized to establish the animal model of overlap syndrome.
Acceleration ; Animals ; Charcoal ; Colon* ; Corticotropin-Releasing Hormone ; Dyspepsia ; Guinea Pigs* ; Guinea* ; Humans ; Irritable Bowel Syndrome ; Models, Animal ; Receptors, Corticotropin-Releasing Hormone ; Water*

BACKGROUND: Microglial cells, major immune effector cells in the central nervous system, become activated in neurodegenerative disorders. Activated microglial cells produce proinflammatory mediators such as nitric oxide (NO), tumor necrosis factor-alpha and interleukin-1beta(IL-1beta). These proinflammatory mediators have been shown to be significantly increased in the neurodegenerative disorders such as Alzhimer's disease and Pakinson's disease. It was known that one of the neurodegeneration source is stress and it is important to elucidate mechanisms of the stress response for understanding the stress-related disorders and developing improved treatments. Because one of the neuropeptide which plays a main role in regulating the stress response is corticotropin- releasing hormone (CRH), we analyzed the regulation of NO release by CRH in BV2 murine microglial cell as macrophage in the brain. METHODS: First, we tested the CRH receptor expression in the mRNA levels by RT-PCR. To test the regulation of NO release by CRH, cells were treated with CRH and then NO release was measured by Griess reagent assay. RESULTS: Our study demonstrated that CRH receptor 1 was expressed in BV2 murine microglial cells and CRH treatment enhanced NO production. Furthermore, additive effects of lipopolysaccaride (LPS) and CRH were confirmed in NO production time dependantly. CONCLUSION: Taken together, these data indicated that CRH is an important mediator to regulate NO release on microglial cells in the brain during stress.
Brain ; Central Nervous System ; Corticotropin-Releasing Hormone* ; Macrophages ; Neurodegenerative Diseases ; Neuropeptides ; Nitric Oxide* ; Receptors, Corticotropin-Releasing Hormone ; RNA, Messenger ; Tumor Necrosis Factor-alpha

High-altitude hypoxia can induce physiological dysfunction and mountain sickness, but the underlying mechanism is not fully understood. Corticotrophin-releasing factor (CRF) and CRF type-i receptors (CRFR1) are members of the CRF family and the essential controllers of the physiological activity of the hypothalamo-pituitary-adrenal (HPA) axis and modulators of endocrine and behavioral activity in response to various stressors. We have previously found that high-altitude hypoxia induces disorders of the brain-endocrine-immune network through activation of CRF and CRFR1 in the brain and periphery that include activation of the HPA axis in a time- and dose-dependent manner, impaired or improved learning and memory, and anxiety-like behavioral change. Meanwhile, hypoxia induces dysfunctions of the hypothalamo-pituitary-endocrine and immune systems, including suppression of growth and development, as well as inhibition of reproductive, metabolic and immune functions. In contrast, the small mammals that live on the Qinghai-Tibet Plateau alpine meadow display low responsiveness to extreme high-altitude-hypoxia challenge, suggesting well-acclimatized genes and a physiological strategy that developed during evolution through interactions between the genes and environment. All the findings provide evidence for understanding the neuroendocrine mechanisms of hypoxia-induced physiological dysfunction. This review extends these findings.
Altitude ; Animals ; Brain ; physiopathology ; Corticotropin-Releasing Hormone ; metabolism ; Hypothalamo-Hypophyseal System ; physiopathology ; Hypoxia ; physiopathology ; Pituitary-Adrenal System ; physiopathology ; Receptors, Corticotropin-Releasing Hormone ; metabolism ; Tibet

BACKGROUND: Corticotropin-Releasing Hormone (CRH), an important regulator of stress response, has a potent immunoregulatory effect with the ability to promote the growth of various cancer through CRH receptor type 1 under stress. Although the metastasized cancers through cell migration are more aggressive than the primary cancers, little is known about the effect of CRH on cell migration. Gastric cancer is prone to metastasize to other tissues and it is reported that gastric cancer is response to various stresses such as oxidative stress. Herein, we studied the relationship between CRH and gastric cancer cell migration. METHODS: We used gastric cancer cell line, MKN-28 and tested the CRH receptor type 1 expression on MKN-28 by RT-PCR. To examine the change in the ability of migration by CRH in MKN-28, cells were incubated with CRH and then migration ability was measured using a cell migration assay. RESULTS: We confirmed that CRH receptor type 1 was expressed in MKN-28 and HaCaT cells. The migration ability of MKN-28 cells was increased by CRH in a time-, dose- dependent manner. CONCLUSION: These data suggest that CRH increases migration ability in gastric cancer cell line and that CRH may be a critical regulator in the metastasis of gastric cancer cell.
Cell Line* ; Cell Migration Assays ; Cell Movement* ; Corticotropin-Releasing Hormone* ; Humans* ; Neoplasm Metastasis ; Oxidative Stress ; Receptors, Corticotropin-Releasing Hormone ; Stomach Neoplasms*

It is well established that increased excitability of the presympathetic neurons in the hypothalamic paraventricular nucleus (PVN) during hypertension leads to heightened sympathetic outflow and hypertension. However, the mechanism underlying the overactivation of PVN presympathetic neurons remains unclear. This study aimed to investigate the role of endogenous corticotropin-releasing factor (CRF) on the excitability of presympathetic neurons in PVN using Western blot, arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) recording, CRISPR/Cas9 technique and patch-clamp technique. The results showed that CRF protein expression in PVN was significantly upregulated in spontaneously hypertensive rats (SHRs) compared with normotensive Wistar-Kyoto (WKY) rats. Besides, PVN administration of exogenous CRF significantly increased RSNA, heart rate and ABP in WKY rats. In contrast, knockdown of upregulated CRF in PVN of SHRs inhibited CRF expression, led to membrane potential hyperpolarization, and decreased the frequency of current-evoked firings of PVN presympathetic neurons, which were reversed by incubation of exogenous CRF. Perfusion of rat brain slices with artificial cerebrospinal fluid containing CRF receptor 1 (CRFR1) blocker, NBI-35965, or CRF receptor 2 (CRFR2) blocker, Antisauvagine-30, showed that blocking CRFR1, but not CRFR2, hyperpolarized the membrane potential and inhibited the current-evoked firing of PVN presympathetic neurons in SHRs. However, blocking CRFR1 or CRFR2 did not affect the membrane potential and current-evoked firing of presympathetic neurons in WKY rats. Overall, these findings indicate that increased endogenous CRF release from PVN CRF neurons enhances the excitability of presympathetic neurons via activation of CRFR1 in SHRs.
Rats ; Animals ; Rats, Inbred SHR ; Paraventricular Hypothalamic Nucleus/physiology* ; Receptors, Corticotropin-Releasing Hormone/metabolism* ; Rats, Inbred WKY ; Corticotropin-Releasing Hormone/metabolism* ; Neurons/physiology* ; Hypertension ; Sympathetic Nervous System

Adverse experiences in early life have long-lasting negative impacts on behavior and the brain in adulthood, one of which is sleep disturbance. As the corticotropin-releasing hormone (CRH)-corticotropin-releasing hormone receptor 1 (CRHR1) system and nucleus accumbens (NAc) play important roles in both stress responses and sleep-wake regulation, in this study we investigated whether the NAc CRH-CRHR1 system mediates early-life stress-induced abnormalities in sleep-wake behavior in adult mice. Using the limited nesting and bedding material paradigm from postnatal days 2 to 9, we found that early-life stress disrupted sleep-wake behaviors during adulthood, including increased wakefulness and decreased non-rapid eye movement (NREM) sleep time during the dark period and increased rapid eye movement (REM) sleep time during the light period. The stress-induced sleep disturbances were accompanied by dendritic atrophy in the NAc and both were largely reversed by daily systemic administration of the CRHR1 antagonist antalarmin during stress exposure. Importantly, Crh overexpression in the NAc reproduced the effects of early-life stress on sleep-wake behavior and NAc morphology, whereas NAc Crhr1 knockdown reversed these effects (including increased wakefulness and reduced NREM sleep in the dark period and NAc dendritic atrophy). Together, our findings demonstrate the negative influence of early-life stress on sleep architecture and the structural plasticity of the NAc, and highlight the critical role of the NAc CRH-CRHR1 system in modulating these negative outcomes evoked by early-life stress.
Animals ; Mice ; Corticotropin-Releasing Hormone/metabolism* ; Nucleus Accumbens/metabolism* ; Receptors, Corticotropin-Releasing Hormone/metabolism* ; Sleep ; Sleep Wake Disorders ; Stress, Psychological/complications*

Major classes of medication in asthma management include bronchodilating beta2-agonists, anti-inflammatory inhaled corticosteroids, leukotriene modifiers and theophyllines. However, all asthmatics do not respond to the same extent to a given medication. Available data suggest that a substantial range of individual variability, as much as 70%, may be due to genetic characteristics of each patient. Pharmacogenomics offers the potential to optimize medications for individual asthmatics by using genetic information to improve efficacy or avoid adverse effects. The best-studied case of the potential contribution of pharmacogenomics to treatment response in asthma comes from studies on human beta2 adrenergic receptors. In addition, genetic variation in beta2-adrenergic receptor (Arg16Gly) may predict response to anticholinergics for the treatment of asthma. In case of inhaled corticosteroids, a recent investigation using a traditional SNP-based approach identified a gene for corticotropin releasing hormone receptor 1 as a potential marker of response. Another major pathway that has been investigated is the pathway underlying response to cysteinyl leukotriene receptor antagonist. It is likely that in the near future, pharmacogenomic approaches based on individual genetic information will be introduced into an asthma treatment guideline and this guideline will allow us to identify those who have the best chance to respond to a specific medication.
Adrenal Cortex Hormones ; Asthma ; Cholinergic Antagonists ; Genes, vif ; Genetic Variation ; Humans ; Pharmacogenetics ; Receptors, Adrenergic ; Receptors, Corticotropin-Releasing Hormone ; Receptors, Leukotriene

Corticotropin-releasing factor (CRF) is a peptide involved in the activation of the hypothalamic-pituitary-adrenal (HPA) axis. CRF is distributed not only along the HPA axis but also throughout pain-relevant anatomical sites. CRF elicits potent antinociception at the three main levels of pain transmissions: namely, the brain, spinal cord, and peripheral sensory neurons. The widespread distribution of CRF receptors 1 and 2 in the brain offers several targets wherein CRF could alter pain, some of which may be independent of the HPA axis. In this study, we assessed the expression of CRF and its receptors, CRF receptor type (CRFR)1 and CRFR2, in the spinal dorsal horn and dorsal root ganglion (DRG) in a rat model of neuropathic pain induced by spinal nerve injury (SNI). CRF was expressed in a few DRG neurons and primary afferent fibers in the dorsal horns of nasmall yi, Ukrainianve rats, and the CRF-positive neurons in DRG and fibers in the spinal dorsal horn were found to have increased after SNI. CRFR1 was not expressed in DRG or the dorsal horn and CRFR2 was expressed weakly in the small neurons in DRG in the nasmall yi, Ukrainianve rats. After SNI, CRFR1 was expressed in the activated microglia in the ipsilateral dorsal horn, and immunoreaction for CRFR2 was increased in the contralateral DRG following SNI. Consequently, it has been suggested that the increased expression of CRF and CRFR2 in DRG neurons and primary afferent fibers in dorsal horn, and CRFR1 in the activated microglia, may be involved in the mediation of stress responses as well as in microglial activation in the neuropathic pain state following SNI.
Animals ; Axis, Cervical Vertebra ; Brain ; Corticotropin-Releasing Hormone ; Diagnosis-Related Groups ; Ganglia, Spinal ; Horns ; Microglia ; Negotiating ; Neuralgia ; Neurons ; Rats ; Receptors, Corticotropin-Releasing Hormone ; Sensory Receptor Cells ; Spinal Cord ; Spinal Nerve Roots ; Spinal Nerves