title: Variation in the ovine cortisol response to systemic bacterial endotoxin challenge is predominantly determined by signalling within the hypothalamic-pituitary-adrenal axis.
abstract: Bi-directional communication between the neuroendocrine and immune systems is designed, in part, to maintain or restore homeostasis during physiological stress. Exposure to endotoxin during Gram-negative bacterial infection for example, elicits the release of pro-inflammatory cytokines that activate the hypothalamic-pituitary-adrenal axis (HPAA). The secretion of adrenal glucocorticoids subsequently down regulates the host inflammatory response, minimizing potential tissue damage. Sequence and epigenetic variants in genes involved in regulating the neuroendocrine and immune systems are likely to contribute to individual differences in the HPAA response, and this may influence the host anti-inflammatory response to toxin exposure and susceptibility to inflammatory disease. In this study, high (HCR) and low (LCR) cortisol responders were selected from a normal population of 110 female sheep challenged iv with Escherichia coli endotoxin (400 ng/kg) to identify potential determinants that contribute to variation in the cortisol response phenotype. This phenotype was stable over several years in the HCR and LCR animals, and did not appear to be attributed to differences in expression of hepatic immune-related genes or systemic pro-inflammatory cytokine concentrations. Mechanistic studies using corticotrophin-releasing factor (0.5 microg/kg body weight), arginine vasopressin (0.5 microg/kg), and adrenocorticotropic hormone (0.5 microg/kg) administered iv demonstrated that variation in this phenotype is largely determined by signalling within the HPAA. Future studies will use this ovine HCR/LCR model to investigate potential genetic and epigenetic variants that may contribute to variation in cortisol responsiveness to bacterial endotoxin.
authors.affiliation: Centre for Genetic Improvement of Livestock, Department of Animal and Poultry Science, University of Guelph, Guelph, Ontario, Canada N1G 2W1.
authors.forename: Qiumei
authors.initials: Q
authors.lastname: You
authors.forename: Niel A
authors.initials: NA
authors.lastname: Karrow
authors.forename: Honghe
authors.initials: H
authors.lastname: Cao
authors.forename: Alexander
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Bonnie A
authors.initials: BA
authors.lastname: Mallard
authors.forename: Herman J
authors.initials: HJ
authors.lastname: Boermans
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D004926:Escherichia coli / Q000276:immunology*; D005260:Female; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics* / Q000276:immunology; D006854:Hydrocortisone / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000276:immunology / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010913:Pituitary-Adrenal System / Q000276:immunology / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep
chemical_list: D016207:Cytokines; D006854:Hydrocortisone