Modeling the effects of estradiol and progesterone on the acute phase proinflammatory axis: Variability in tumor necrosis factor-alpha, nitric oxide, and xanthine oxidase responses to endotoxin challenge in steers

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

Submitted to: Domestic Animal Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/19/2011
Publication Date: 5/1/2011
Citation: Elsasser, T.H., Kahl, S., Li, C. 2011. Modeling the effects of estradiol and progesterone on the acute phase proinflammatory axis: Variability in tumor necrosis factor-¿, nitric oxide, and xanthine oxidase responses to endotoxin challenge in steers. Domestic Animal Endocrinology. 40(4):213-221.

Interpretive Summary: Much controversy surrounds the issue of whether gender plays a role in the sysceptibility of cattle to diseases. Not only is gender per se a question in this regard but also are the potential consequences on cattle health of the use of hormonally active compounds for growth promotion that modify an animal’s hormonal balance through, for example, the use of estrogen, progesterone, zeranol, and trenbolone acetate usually in combinations. The present study used steers to study how low-level supplementation with estrogen alone or progesterone to mimic ordinary physiological levels on changes in key biomarkers of the inflammatory response to bacterial cell wall endotoxin. We chose four indicators of response to measure each of which probed a different level of the proinflammatory response: tumor necrosis factor-a as an indicator of cytokine initiating factors, nitric oxide as an indicator of immune communication, xanthine oxidase as a marker for superoxide anion generating enzymes and haptoglobin as a recovery marker. Two separate administrations of endotoxin were given to each steer to test whether normal patterns of tolerance to repeated proinflammatory exposures took place. The data indicated that across the various mediators, progesterone depressed and estradiol augmented production of the responding biomarkers. The tolerance/downregulation response was preserved in the presence of progesterone while the ability to down regulate was lost with the estrogen treatment. The data suggest that some aspects of the select responses to bacterial infection may be selectively modulated by the administration of low levels of estrogen or progesterone to steers.

Technical Abstract: The severity of host response in some diseases differs between sexes and this dimorphism has been attributed to the immunomodulating effects of reproductive steroid hormones. In females, susceptibility to disease stress has been associated with reproductive status and attributed to prevailing progesterone (P4) or estrogen concentrations during different estrous cycle phases. Our objective was to clarify and define the effect of P4 or 17ß-estradiol (E2) on the acute proinflammatory component of the innate immune system by administering these hormones to steers and evaluating initial and tolerance-associated concentration patterns of circulating proinflammatory immune response mediators after two consecutive LPS challenges (LPS1 and LPS2, 6 d apart; 2.5 µg/kg BW, i.v., E. coli 055:B5). Plasma concentrations of the proinflammatory initiation cytokine tumor necrosis factor-a (TNF-'), nitrate+nitrite (NOx, estimate of NO production), haptoglobin (HG, acute phase protein), and plasma xanthine oxidase activity (XO, mediator of superoxide production), were measured. Crossbred steers (392 ± 7 kg) were fed a forage-concentrate diet (15% CP) to appetite and assigned to control (C, n = 7), P4 (n = 8) or E2 (n = 5) treatment. Jugular blood samples were obtained at 0, 1, 2, 3, 4, 7, and 24 h relative to each of the 2 LPS injections. For each proinflammatory biomarker, the area under the time × concentration curve (AUC) was used to evaluate and compare responses to the LPS challenge. Treatment with E2 disrupted LPS tolerance as observed in augmented plasma TNF-a (P < 0.01) and NOx (P < 0.01) responses to LPS2. Compared to C, P4 treatment decreased plasma NOx AUC after LPS2 (P < 0.05) and tended to reduce TNF-a AUC after LPS1 (P = 0.08). Plasma XO AUC was increased (P < 0.01) over C by E2 treatment after both LPS1 and LPS2. HG response to LPS1 within 24 h was not affected by any treatment. However, 6 d after LPS1 plasma HG concentration remained higher (P < 0.01) in steers treated with E2 than C or P4. Results indicate that in cattle, P4 and E2, respectively, attenuate or amplify the response to LPS challenge at several points critical to the regulation of the progression of the proinflammatory cascade.