Corticotropin-releasing hormone regulates IL-6 expression during inflammation
Journal of Clinical InvestigationPublished 15 October 2001Open access
Maria Venihaki, Pieter Dikkes, Allison Carrigan, Katia Karalis
Citations128
SJR quartileQ1
SJR score4.72
SNIP2.17
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TL;DR
The findings suggest that during inflammation, IL-6 most likely compensates for the effects of CRH deficiency on food intake, and support the importance of the interaction between the immune system and the HPA axis in the pathophysiology of inflammatory diseases.
Abstract
Stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by proinflammatory cytokines results in increased release of glucocorticoid that restrains further development of the inflammatory process. IL-6 has been suggested to stimulate the HPA axis during immune activation independent of the input of hypothalamic corticotropin-releasing hormone (CRH). We used the corticotropin-releasing hormone-deficient (Crh(-/-)) mouse to elucidate the effect of CRH deficiency on IL-6 expression and IL-6-induced HPA axis activation during turpentine-induced inflammation. We demonstrate that during inflammation CRH is required for a normal adrenocorticotropin hormone (ACTH) increase but not for adrenal corticosterone rise. The paradoxical increase of plasma IL-6 associated with CRH deficiency suggests that IL-6 release during inflammation is CRH-dependent. We also demonstrate that adrenal IL-6 expression is CRH-dependent, as its basal and inflammation-induced expression is blocked by CRH deficiency. Our findings suggest that during inflammation, IL-6 most likely compensates for the effects of CRH deficiency on food intake. Finally, we confirm that the HPA axis response is defective in Crh(-/-)/IL-6(-/-) mice. 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.
Keywords
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The Journal of Experimental MedicineDefective inflammatory response in interleukin 6-deficient mice.
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Annual Review of ImmunologyNeuroendocrine-Immune System Interactions and Autoimmunity
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These factors and dysfunctional communication between the nervous, endocrine, and immune systems appear to contribute to the development of autoimmune diseases in the Lewis and BB rats, the OS chicken, and the NOD, MRL, NZB, NZW, and NZB/NZW F1 mice.
Biochemical and Biophysical Research CommunicationsInterleukin-6 stimulates the secretion of adrenocorticotropic hormone in conscious, freely-moving rats
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NatureCorticotropin releasing factor induction of leukocyte-derived immunoreactive ACTH and endorphins
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It is reported that the production of ACTH and endorphins by leukocytes is indeed induced by synthetic CRF10 and, in turn, suppressed by dexamethasone, suggesting that, as in pituitary cells, the pro-opiomelanocortin (POMC) gene may be expressed and similarly controlled in leukocyte.
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British Journal of CancerThe relationship between weight loss and interleukin 6 in non-small-cell lung cancer
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It is clear that there is a differential sensitivity of various populations and subpopulations of cells to the corticosteriod modulation of cellular kinetic patterns, cellular interactions, and functional capabilities.
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Journal of NeurochemistryDifferential Involvement of Central and Peripheral Norepinephrine in the Central Lipopolysaccharide‐Induced Interleukin‐6 Responses in Mice
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CytokineINTERLEUKIN 6, BUT NOT CILIARY NEUROTROPHIC FACTOR OR LEUKAEMIA INHIBITORY FACTOR, IS RESPONSIBLE FOR THE ACUTE PHASE RESPONSE TO TURPENTINE-INDUCED MYOSITIS
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