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Veterinary immunology and immunopathology2008; 129(3-4); 192-199; doi: 10.1016/j.vetimm.2008.11.006

Role of p38 MAPK in LPS induced pro-inflammatory cytokine and chemokine gene expression in equine leukocytes.

Abstract: Endotoxemia occurs when bacterial lipopolysaccharide (LPS) in the blood induces a dysregulated inflammatory response, resulting in circulatory shock and multi-organ failure. Laminitis is a common complication in endotoxemic horses and is frequently the reason for humane euthanasia of these cases. Blood leukocytes are a principal target of LPS in endotoxemia leading to activation of multiple signal transduction pathways involved in the induction of a number of pro-inflammatory genes. In other animal models, the p38 mitogen activated protein kinase (MAPK) pathway has been associated with induced expression of tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-1beta, IL-6 and IL-8. The goal of this study was to determine the role of the p38 MAPK pathway in the induction of these pro-inflammatory cytokine and chemokine genes in LPS-stimulated equine leukocytes. Stimulation of equine peripheral blood leukocytes resulted in an increase in TNFalpha, IL-1beta, IL-6 and IL-8 mRNA levels. Pharmacological inhibition of p38 MAPK activity with SB203580 or SB202190 reduced the ability of LPS stimulation to increase mRNA concentrations for all four genes. However, only SB203580 pretreatment significantly reduced LPS-stimulated IL-1beta and IL-8 mRNA expression and only pretreatment with SB202190 significantly reduced LPS-stimulated TNFalpha and IL-6 mRNA expression. From this study we conclude TNFalpha, IL-1beta, IL-6 and IL-8 are induced upon LPS stimulation of equine leukocytes and that this induction of gene expression is dependent on the p38 MAPK pathway. However, there are differences in the efficacy of the p38 inhibitors tested here that may be explained by differences in specificity or potency. This study provides evidence for the use of selective p38 MAPK inhibitors as potential therapeutics for the treatment of equine endotoxemia.
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Publication Date: 2008-11-07 PubMed ID: 19070370DOI: 10.1016/j.vetimm.2008.11.006Google Scholar: Lookup
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  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article presents a study on equine (horse) immune response, focusing on triggering inflammatory reactions through a certain pathway (p38 MAPK). The study investigates how blocking this pathway might affect inflammation response in horses, crucially looking at whether potential treatments for equine endotoxemia – a severe, life-threatening condition – could be developed.

Understanding the biochemical context: p38 MAPK

  • When horses undergo endotoxemia, an excessive inflammatory reaction to bacterial lipopolysaccharides (LPS) in the blood, they may experience circulatory shock or multi-organ failure. It can also lead to a complication called laminitis, which often necessitates euthanasia.
  • The immune cells in the blood, or leukocytes, respond to LPS by triggering multiple pathways in the cell, including the p38 mitogen-activated protein kinase (MAPK) pathway.
  • In other animal models, the p38 MAPK pathway is often associated with the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-1beta, IL-6, and IL-8.

Investigating p38 MAPK’s involvement in inflammation

  • The researchers undertook to understand the role of the p38 MAPK pathway in inducing these pro-inflammatory cytokines and chemokines in equine leukocytes when stimulated by LPS.
  • Experiments involving the stimulation of equine peripheral blood leukocytes provided proof that this stimulation led to an increase in TNFalpha, IL-1beta, IL-6, and IL-8 mRNA levels.
  • They also utilized pharmacological inhibition of the p38 MAPK pathway using two agents – SB203580 and SB202190. They found that inhibiting the p38 MAPK pathway reduced the resultant increase in mRNA concentrations related to the four cytokines.

Specific responses to p38 inhibitors and concluding remarks

  • Interestingly, only SB203580 significantly reduced the IL-1beta and IL-8 mRNA expression triggered by LPS, while SB202190 effectively lowered the LPS-stimulated TNFalpha and IL-6 mRNA expression.
  • From this, the researchers concluded that the expression of TNFalpha, IL-1beta, IL-6, and IL-8, which is typically induced by the presence of LPS, relies on the p38 MAPK pathway. Discrepancies observed in how the two inhibitors functioned could be chalked up to differences in specificity or potency.
  • The findings of this study lend support to the potential use of selective p38 MAPK inhibitors as therapeutic treatments for equine endotoxemia, a severe and often fatal illness in horses.

Cite This Article

APA
Neuder LE, Keener JM, Eckert RE, Trujillo JC, Jones SL. (2008). Role of p38 MAPK in LPS induced pro-inflammatory cytokine and chemokine gene expression in equine leukocytes. Vet Immunol Immunopathol, 129(3-4), 192-199. https://doi.org/10.1016/j.vetimm.2008.11.006

Publication

Veterinary immunology and immunopathology
ISSN: 0165-2427
NlmUniqueID: 8002006
Country: Netherlands
Language: English
Volume: 129
Issue: 3-4
Pages: 192-199

Researcher Affiliations

Neuder, Laura E
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, United States.
Keener, Jamie M
    Eckert, Rachael E
      Trujillo, Jennifer C
        Jones, Samuel L

          MeSH Terms

          • Animals
          • Cells, Cultured
          • Chemokines / genetics
          • Chemokines / metabolism
          • Cytokines / genetics
          • Cytokines / metabolism
          • Gene Expression Regulation / physiology
          • Horses / blood
          • Horses / immunology
          • Horses / metabolism
          • Leukocytes / drug effects
          • Leukocytes / metabolism
          • Lipopolysaccharides / pharmacology
          • RNA, Messenger / metabolism
          • Signal Transduction / drug effects
          • Signal Transduction / physiology
          • p38 Mitogen-Activated Protein Kinases / metabolism

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