A Novel Role of Peripheral Corticotropin-Releasing Hormone (CRH) on Dermal Fibroblasts

Corticotropin-releasing hormone, or factor, (CRH or CRF) exerts important biological effects in multiple peripheral tissues via paracrine/autocrine actions. The aim of our study was to assess the effects of endogenous CRH in the biology of mouse and human skin fibroblasts, the primary cell type involved in wound healing. We show expression of CRH and its receptors in primary fibroblasts, and we demonstrate the functionality of fibroblast CRH receptors by induction of cAMP. Fibroblasts genetically deficient in Crh (Crh−/−) had higher proliferation and migration rates and compromised production of IL-6 and TGF-β1 compared to the wildtype (Crh+/+) cells. Human primary cultures of foreskin fibroblasts exposed to the CRF1 antagonist antalarmin recapitulated the findings in the Crh−/− cells, exhibiting altered proliferative and migratory behavior and suppressed production of IL-6. In conclusion, our findings show an important role of fibroblast-expressed CRH in the proliferation, migration, and cytokine production of these cells, processes associated with the skin response to injury. Our data suggest that the immunomodulatory effects of CRH may include an important, albeit not explored yet, role in epidermal tissue remodeling and regeneration and maintenance of tissue homeostasis

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: A comparative risk assessment

Background: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. Findings: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. Funding: UK Medical Research Council, US National Institutes of Health. © 2014 Elsevier Ltd

Corticotropin releasing hormone (CRH) in peripheral inflammation

Corticotropin releasing hormone (CRH) is a major mediator of the stress reaction, via stimulation of ACTH, corticosteroids and catecholamines release. All the above hormones and peptides tend to inhibit the immune-inflammatory response and keep the homeostasis during the immune stress. We hypothesized that CRH is released from peripheral sources during the inflammatory response and exerts biological effects. We used three experimental updels of inflammation: the carrageenin-induced acute aseptic inflammation, and the streptococcal-cell wall (SCW) and mycobacterium-induced arthritis CRH was identified by immunohistochemistry in sections of the inflammed tissues and characterized and quantitated by HPLC and RIA. PCR was used to identify the source of peripheral CRH. The biological action of CRH was examined using anti-CRH antiserum to immunoneutralize the endogenous CRH and our findings suggested pro-inflammatory action of the peripheral CRH, acting possibly as a counter-balance of the anti-inflammatory central CRH. Finally, peripheral CRH was identified in synovium and synovial fluid of patients with rheumatoid arthritis (RA) and osteoarthritis.Επικοινωνία μεταξύ του ανοσολογικού ενδοκρινικού και νευρικού συστήματος επιτυγχάνει τη διατήρηση της ομοιοστασίας του οργανισμού κάτω από συνθήκες στρες. Νευροπεπτίδια και λεμφοκίνες, που είναι τα χυμικά εκλυτικά προϊόντα αυτών των συστημάτων, αποτελούν τη μοριακή βάση στήριξης της επικοινωνίας τους. Η εκλυτική ορμόνη της κορτικοτροπίνης (CRH) αποτελεί ένα από τους σημαντικότερους μεταβιβαστές της αντίδρασης στρες, προκαλώντας έκλυση ACTH και γλυκοκορτικοειδών από τον υποφυσιακό-επινεφριδιακό άξονα και κατεχολαμινών από το κεντρικό και περιφερικό νευρικό σύστημα. Η διέγερση του ανοσολογικού συστήματος συνιστά κατάσταση στρες και η προσπάθεια του οργανισμού να το υπερβεί εκδηλώνεται με την ανάπτυξη φλεγμονώδους αντίδρασης. Μελετήσαμε την έκλυση CRH από περιφερικούς φλεγμαίνοντες ιστούς ανθρώπων και επίμυων. Τα ευρήματα μας αποδεικνύουν έκλυση βιολογικά ενεργής CRH τοπικά σε φλεγμαίνοντες ιστούς και σύνθεση της από κύτταρα του ανοσολογικού συστήματος. Η περιφερική CRH φαίνεται ότι ασκεί άμεση προφλεγμονώδη δράση, αντισταθμίζοντας την έμμεση, μέσω έκλυσης γλυκοκορτικοειδών και κατεχολαμινών, ανοσοκατασταλτική δράση της κεντρικής CRH

Neural stem cells respond to stress hormones: distinguishing beneficial from detrimental stress

Neural stem cells (NSCs), the progenitors of the nervous system, control distinct, position-specific functions and are critically involved in the maintenance of homeostasis in the brain. The responses of these cells to various stressful stimuli are shaped by genetic, epigenetic, and environmental factors via mechanisms that are age and developmental stage-dependent and still remain, to a great extent, elusive. Increasing evidence advocates for the beneficial impact of the stress response in various settings, complementing the extensive number of studies on the detrimental effects of stress, particularly in the developing brain. In this review, we discuss suggested mechanisms mediating both the beneficial and detrimental effects of stressors on NSC activity across the lifespan. We focus on the specific effects of secreted factors and we propose NSCs as a “sensor,” capable of distinguishing among the different stressors and adapting its functions accordingly. All the above suggest the intriguing hypothesis that NSCs are an important part of the adaptive response to stressors via direct and indirect, specific mechanisms