|Elsasser, Theodore - Ted|
Submitted to: Journal of Animal Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/28/2004
Publication Date: 5/17/2005
Citation: Daniel, J.A., Elsasser, T.H., Martinez, A., Steele, B., Whitlock, B.K. Sartin, J.L. 2005. Interleukin-1B and tumor necrosis factor-a mediation of endotoxin action on growth hormone. American Journal of Physiology:Endocrinology and Metabolism. Available: http//ajpendo.physiology.org/cgi/reprint/00489.2004vl. Interpretive Summary: The ability to regulate metabolism when animals are stressed by infection or general disease depends on an accurate assessment of factors that can be controlled to minimize adverse impact on the animal. A previous model of infection stress suggested that alterations in metabolism occur because in the animal's response to infection, its immune system could release immune hormones called cytokines that regulated metabolic hormone secretion through receptors for these cytokines directly on the hormone secreting cell. The present experiment altered this view. We used sheep as a model and mimicked an infection with the administration of extracts of bacterial cell walls thus eliminating the need to actually infect the animal. The data demonstrated that the bacterial toxin called endotoxin could interact directly with cells of the pituitary gland that secrete the metabolic hormone growth hormone through the presence of a binding complex specifically called CD-14 on the GH-secreting cell. With this knowledge, intervention strategies to limit the impact of disease on metabolism could be sought through the development of compounds that might block the interaction of endotoxin with the CD-14.
Technical Abstract: In humans and sheep, administration of endotoxin results in increased concentrations of growth hormone (GH). Experiments were designed to determine the mechanism by which endotoxin increases concentrations of GH. To determine if cytokines mediated the effect of endotoxin on GH, sheep were challenged with interleukin-1b (IL-1) or tumor necrosis factor-a (TNF). Intracerebroventricular (icv) administration of IL-1 or TNF did not alter plasma concentrations of GH relative to saline treated animals. Endotoxin or saline was then administered in combination with IL-1 antagonist (IL-1ra), TNF antagonist (sTNF-R1), or saline. Administration of endotoxin increased plasma concentrations of GH, while co-administration of IL-1ra or sTNF-R1 icv did not effect endotoxin stimulation of GH. Intravenous administration of either IL-1 and TNF increased plasma concentrations of GH. Administration of IL-1ra and sTNF iv prevented endotoxin induced increases in GH. To determine if the pituitary could respond directly to endotoxin, presence of the endotoxin binding molecule, CD14, was determined in pituitaries collected from sheep 4 hr following iv challenge with saline or endotoxin. Confocal microscropcy revealed that GH co-localized with CD14 in saline and endotoxin treated animals. These data indicate that IL-1 and TNF mediate endotoxin's effect to increase GH secretion on a peripheral level.