Cousillas, Georgina2018-11-282018-11-282018-08https://hdl.handle.net/11299/201059University of Minnesota Ph.D. dissertation.August 2018. Major: Animal Sciences. Advisor: Brian Crooker. 1 computer file (PDF); xiv, 259 pages.Studies were designed to assess the impact of milk yield genotype on the innate immune response and its interactions with endocrine and metabolic components when growing heifers and lactating cows are challenged with lipopolysaccharide (LPS). A novel aspect of these studies was the comparison of unique Holsteins that have not been subjected to selection since 1964 (unselected Holsteins; UH) with contemporary Holsteins (CH). In addition, our animal models included heifers from contemporary Red-Black Angus cows (CA) and our experimental designs included the use of repeated LPS administration to assess the impact of genotype on the acute immune response and on the development of a refractory (endotoxin tolerance) state. Pro-inflammatory cytokine and glucose concentrations were greater and cortisol concentrations increased more rapidly in Holsteins than in Angus heifers which is consistent with results from our collaborators that indicate Holsteins have a more robust immune response than Angus cattle. Differences in plasma concentrations of pro-inflammatory cytokines, glucose and cortisol, and in expression of adhesion molecules and phagocytic activity of polymorphonuclear leukocytes (PMNL) after LPS administration indicates UH heifers and cows have a more robust immune response than CH heifers and cows. This was further supported by hepatic gene expression data, which indicated greater expression of genes in the TLR4 signaling pathway and of genes involved in the production of pro and anti-inflammatory mediators (IL6, TNF, IL1RN, TGFB1) in UH than in CH cows during the acute immune response. In addition, results during the second challenge indicated greater development of tolerance to immunotoxin stimulation in UH than CH cows. Overall, our results demonstrate that TLR4 signaling pathways have been altered by five decades of selective breeding and these changes contribute to a less robust and less controlled innate immune response in CH cows. Thus, immune activation and the ability to minimize negative effects of prolonged inflammation are reduced in the CH cow. Although we did not assess the impact of selection, we assessed functionality of several anti-ADAM17 antibodies and inhibitors and for, the first time, characterized the presence and activity of ADAM17 (a disintegrin and metalloproteinase-17) protein in bovine PMNL.enADAM17bovine genotypedairygene expressionimmunitylipopolysaccharide (LPS)Thesis or Dissertation