Variability in tumor necrosis factor-alpha, nitric oxide, and xanthine oxidase responses to endotoxin challenge in heifers: Effect of estrous cycle stage

Authors: Kahl, Stanislaw; Elsasser, Theodore; Li, Congjun - Cj

Submitted to: Domestic Animal Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/23/2008
Publication Date: 1/20/2009
Citation: Kahl, S., Elsasser, T.H., Li, C. 2009. Variability in tumor necrosis factor-alpha, nitric oxide, and xanthine oxidase responses to endotoxin challenge in heifers: Effect of estrous cycle stage. Domestic Animal Endocrinology. 36:82-88.

Interpretive Summary: We performed experiments aimed at understanding how reproductive status of cows affects their ability to react to immune challenge. Cows were injected with a synthetic prostaglandin prior to use in an experiment in order to establish defined estrus and diestrus stages of the estrus cycle. Immune challenge was modeled with endotoxin injection and plasma samples analyzed for critical biomarkers of the proinflammatory response that previously in our laboratory were validated as relevant to the severity of an animal’s individual response. Data indicated that the diestrus stage of the cycle, where progesterone dominates the reproductive hormone milieu, depressed the intensity of immune response to endotoxin as measured by lower plasma concentrations of tumor necrosis factor-alpha, glucose, nitric oxide, and xanthine oxidase but higher concentrations of cortisol than measured in cows in the estrus stage of the cycle. Collectively, the data suggest that animals in the diestrus stage of the estrus cycle may be more prone to increased severity of response to bacterial infection that at other stages of the estrus cycle similar to the response of animals considered immunocompromised during parturition.

Technical Abstract: The severity of host response to some disease agents differs between sexes and this dimorphism has been attributed to the immunomodulating effects of steroid hormones. Our objective was to determine in heifers whether the phase of estrous cycle affected immune response mediators after endotoxin challenge (LPS, 2.5 µg/kg BW, i.v.). Sixteen beef heifers (426 ± 9 kg) were reproductively synchronized with the two-injection protocol of dinoprost tromethamine (Lutalyse®, Pfizer) to establish diestrus and estrus stages of the estrous cycle. Heifers were challenged with LPS on day 3 (E, estrus; n = 8) or day 10 (D, diestrus, n=8) after the last i.m. injection of Lutalyse®. In all heifers, plasma concentrations of tumor necrosis factor-' (TNF-') peaked 2 h after LPS (P< 0.01) and returned to basal level by 7 h. However, the integrated TNF-' response (area under the time × concentration curve, AUC) was greater in E than in D (P < 0.05). Plasma concentrations of nitrate+nitrite (NOx, an estimate of NO production) increased (P < 0.01) in all heifers at 7 and 24 h after LPS; plasma NOx AUC after LPS was greater in E than D (P < 0.01). Plasma xanthine oxidase activity (XO, a mediator of superoxide production) responses were also greater in E than D (P < 0.05). A companion LPS challenge study in steers validated that the protocol for and use of Lutelyse® did not affect any of the immune parameters studied in heifers in response to LPS. Results indicate that the underlying physiological attributes of the estrus and diestrus phases of the estrous cycle constitute a major source of variability in the magnitude of proinflammatory response to bacterial toxins like LPS.