CRH AND INNATE IMMUNITY · Corticotropin Releasing Hormone (CRH) and Innate Immune responses to Gram negative Bacteria
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2005-06-01 → 2007-05-31
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- IRG
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Results in brief
Final Activity Report Summary - CRH AND INNATE IMMUNITY (Corticotropin Releasing Hormone (CRH) and Innate Immune responses to Gram negative Bacteria)
All organisms are faced with a variety of challenges from the external environment that are collectively referred as stressors. The response to these stressors constitutes an adaptive mechanism coordinated by a component of the endocrine system, the hypothalamic-pituitray-adrenal (HPA) axis. This system includes a part in the central nervous system that secretes two hormones Corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH), and a component in the body, the adrenal glands, that release glucocorticoid. One of the major stressors for the organism is its challenge by pathogenic organisms that can cause infection and inflammation. The organism recognizes its invasion by the different organisms via specific families of receptors including Toll-like receptors (TLRs), that when activated by a pathogen initiate a series of events that ends with the production by the organism of factors termed cytokines that are involved in the development of further disease. It has been described by a variety of investigators that pathogens activate the stress response, shown by increased levels of glucocorticoid in the blood. In this study we evaluated the hypothesis that HPA axis and the cascade of activation of TLR4, a receptor that recognizes a big family of harmful bacteria, the Gram negative, interact to coordinate the response to these organisms. In addition, we evaluated the exact level(s) of their interaction at the cellular level. We believe that characterisation of the molecular mechanisms of interaction of these systems will provide new insights in the development of specific therapeutic regimens for this serious group of infections that can often result in the development of endotoxemia and sepsis.
Data: CORDIS, © European Union
Project objective
Several studies support the interaction between the endocrine and the immune systems during inflammation and have demonstrated the critical role of the hypothalamic-pituitary-adrenal (HPA) axis in this process.We have demonstrated proinflammatory effects of Corticotropin Releasing Hormone (CRH) in vivo and we have confirmed these findings by the compromised inflammatory responses of the Crh-deficient (Crh-/-) mice to a variety of stimuli.We have also shown reduced proinflammatory cytokine expression and lower NF-B activation in Crh-/- splenocytes exposed to lipopolysaccharide (LPS), and induction of NF-B activity by CRH in mouse thymocytes.Although the above findings indicate a pathway mediating the proinflammatory effects of CRH, the signalling pathways involved in the CRH-induced NF-B activation and up-regulation of proinflammatory cytokines remain elusive.Our working hypotheses are that the proinflammatory effects of CRH during Gram-negative infection are mediated by the I-B/NF-B and the MAP kinases systems and that CRH plays a role in the molecular regulation of the expression of Toll-like receptor (TLR)-4, that is critical in the transduction of the lipopolysaccharide (LPS) signalling inside the cells.Mouse and human macrophage cell lines, and primary cells from Crh-/- mice will be used to address the following:- Does CRH play a role in the regulation of TLR4 or its effects are exerted at the level of the adapter proteins and/or transcription factors activated by this receptor? What is the biological significance of the CRH-induced TLR4 regulation on the transcriptional activation of proinflammatory mediators of Gram negative infections?- What is the effect of Crh-deficiency on the molecular regulation of TLR4 expression? The overall significance of this proposal is related to our understanding on the participation of CRH, a representative neuropeptide with immunomodulatory properties, in the regulation of the innate responses to Gram-negative bacteria the cause of infections associated wit h high morbidity.
Original text from CORDIS.
Participants
- FOUNDATION FOR BIOMEDICAL RESEARCH OF THE ACADEMY OF ATHENS · ATHENSCoordinatorCity levelGreece
Links
Data: CORDIS, © European Union