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

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, 2.5microg/kg BW, i.v.). Sixteen beef heifers (426+/-9kg) 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-alpha (TNF-alpha) peaked 2h after LPS treatment (P<0.01) and returned to basal level by 7h. However, the integrated TNF-alpha response (area under the time x concentration curve, AUC) was greater in E than in D (P<0.05). Plasma concentrations of nitrate+nitrite (NO(x), an estimate of NO production) increased (P<0.01) in all heifers at 7 and 24h after LPS; plasma NO(x) 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 Lutalyse 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.