Abstract
Excessive stimulation of the TLR4 axis through LPS reduces the expression of some cytokine genes in immune cells, while stimulating the expression of immune defense genes during a subsequent bacterial infection. This endotoxin tolerance (ET) is mediated via epigenetic mechanisms. Priming the udder of cows with LPS was shown to induce ET in mammary epithelial cells (MEC), thereby protecting the udder against reinfection for some time. Seeking alternatives to LPS priming we tried to elicit ET by priming MEC with either lipopeptide (Pam2CSK4) via the TLR2/6 axis or inhibitors of histone-modifying enzymes. Pre-incubation of MEC with Pam2CSK4 enhanced baseline and induced expression of bactericidal (β-defensin; SLPI) and membrane protecting factors (SAA3, TGM3), while reducing the expression of cytokine- and chemokine-encoding genes (TNF, IL1β) after a subsequent pathogen challenge, the latter, however, not as efficiently as after LPS priming. Pre-treating MEC with various inhibitors of histone H3 modifiers (for demethylation, acetylation or deacetylation) all failed to induce any of the protective factors and only resulted in some dampening of cytokine gene expression after the re-challenge. Hence, triggering immune functions via the TLR axis, but not through those histone modifiers, induced the beneficial phenomenon of ET in MEC.
Highlights
Inflammation and infection of the udder is a frequent and highly relevant disease in dairy farming.[1]
We found that LPS priming induced ‘endotoxin tolerance’ (ET) in mammary epithelial cells (MEC) was the likely cause underpinning the reduced infection probability and milder symptoms during a subsequent
We explored the value of the synthetic TLR2/6 ligand, Pam2CSK4,29 as a model substance for derivatives of bacterial lipopeptides or lipoproteins to induce ET in MEC
Summary
Inflammation and infection of the udder (mastitis) is a frequent and highly relevant disease in dairy farming.[1] Infections of Gram-negative pathogens, such as Escherichia coli, frequently cause severe inflammation and clinical symptoms.[2,3] The risk of suffering from a new udder infection is by far highest during the first 2 wk after calving,[4] only during a limited period of time. It is appealing to search for treatments that protect the udder against infection during that critical and timely limited period. Such treatments are best not based on the application of antibiotics. The treatment provided a longer lasting (10 d) protection against severe systemic symptoms in the case of a successful reinfection.[5]
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