Impact of Glucocorticoids on TNFα Responses after Pathogen- and Damage-associated Molecular Pattern Stimulation of Bovine Leukocytes
Date
2023-04-24
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Thesis
Degree Level
Masters
Abstract
Infectious diseases are responsible for significant economic losses to the livestock industry, affecting animal health, welfare, and performance. With increasing regulations against the use of antibiotics in livestock, there is a need to identify alternative strategies to minimize the susceptibility of animals to infection. While there is an appreciation that stress may impact susceptibility to infectious disease, there is contradictory evidence that stress can act to suppress or enhance immune activity and these immune consequences are influenced by type and duration of the stressor. Therefore, it is important to understand the functional consequences of stress on the immune system and the mechanisms by which stress alters immune function. To this end, we investigated the effect of stress on innate immune responses to molecules associated with pathogens and host cell damage. Bovine peripheral blood mononuclear cells (PBMCs) were stimulated ex vivo with lipopolysaccharide (LPS), peptidoglycan (PGN), and high mobility group box 1 (HMGB1), known agonists for pattern recognition receptors (PRR). The pathogen- and damage-associated molecular patterns (PAMPs and DAMPs, respectively) agonists, were used to simulate exposure to infection and host damage. These stimulations were performed either with or without PBMC pre-treatment with the prototypical stress hormone hydrocortisone to mimic a stress response. Tumor necrosis factor alpha (TNFα) release was used to quantify the innate immune response to each PAMP or DAMP and our results determined the kinetics of TNFα release in response to LPS, PGN, and HMGB1. Our study found increased release of TNFα after stimulation with all ligands, with a delayed response for PBMCs stimulated with PGN. Pre-treatment of cells with hydrocortisone significantly (p<0.05) inhibited TNFα release in a dose-dependent manner, but maximal corticosteroid inhibition was only ~50%. This plateau in corticosteroid inhibition was consistent with all PAMPs and the DAMP. These results demonstrate that a fraction of the TNFα released by bovine PBMCs following exposure to PAMPs and DAMPs can be inhibited by hydrocortisone, but this inhibition is not significant at the level of gene transcription. Our results suggest an acute stress response which elevates corticosteroids may partially inhibit TNFα responses induced by either pathogens or host cell damage. It remains to be determined whether this inhibition of PRR signaling results in increased susceptibility to infection and disease or reduces the risk of immune-mediated pathology.
Description
Keywords
glucocorticoids, TNFα, bovine, leukocytes, PBMCs, pathogen-associated molecular patterns, damage-associated molecular patterns, stress, hydrocortisone, cortisol, peptidoglycan, lipopolysaccharide, HMGB1, TACE
Citation
Degree
Master of Science (M.Sc.)
Department
Biochemistry
Program
Biochemistry