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Frontiers in veterinary science2017; 4; 160; doi: 10.3389/fvets.2017.00160

Misoprostol Inhibits Lipopolysaccharide-Induced Pro-inflammatory Cytokine Production by Equine Leukocytes.

Abstract: Pro-inflammatory cytokines including tumor necrosis factor α (TNFα), IL-1β, IL-6, and IL-8 are potent immune mediators that exacerbate multiple equine diseases such as sepsis and laminitis. Unfortunately, safe and effective cytokine-targeting therapies are lacking in horses; therefore, novel mechanisms of inhibiting cytokine production are critically needed. One potential mechanism for inhibiting cytokine synthesis is elevation of intracellular cyclic AMP (cAMP). In human leukocytes, intracellular cAMP production is induced by activation of E-prostanoid (EP) receptors 2 and 4. These receptors can be targeted by the EP2/4 agonist and prostaglandin E analog, misoprostol. Misoprostol is currently used as a gastroprotectant in horses but has not been evaluated as a cytokine-targeting therapeutic. Thus, we hypothesized that misoprostol treatment would inhibit pro-inflammatory cytokine production by lipopolysaccharide (LPS)-stimulated equine leukocytes in an inflammation model. To test this hypothesis, equine leukocyte-rich plasma (LRP) was collected from 12 healthy adult horses and used to model LPS-mediated inflammatory signaling. LRP was treated with varying concentrations of misoprostol either (pretreated) or (posttreated) LPS stimulation. LRP supernatants were assayed for 23 cytokines using an equine-specific multiplex bead immunoassay. Leukocytes were isolated from LRP, and leukocyte mRNA levels of four important cytokines were evaluated RT-PCR. Statistical differences between treatments were determined using one-way RM ANOVA (Holm-Sidak testing) or Friedman's RM ANOVA on Ranks (SNK testing), where appropriate ( < 0.05,  = 3-6 horses). These studies revealed that misoprostol pre- and posttreatment inhibited LPS-induced TNFα and IL-6 protein production in equine leukocytes but had no effect on IL-8 protein. Interestingly, misoprostol pretreatment enhanced IL-1β protein synthesis following 6 h of LPS stimulation, while misoprostol posttreatment inhibited IL-1β protein production after 24 h of LPS stimulation. At the mRNA level, misoprostol pre- and posttreatment inhibited LPS-induced TNFα, IL-1β, and IL-6 mRNA production but did not affect IL-8 mRNA. These results indicate that misoprostol exerts anti-inflammatory effects on equine leukocytes when applied before or after a pro-inflammatory stimulus. However, the effects we observed were cytokine-specific and sometimes differed at the mRNA and protein levels. Further studies are warranted to establish the inhibitory effects of misoprostol on equine cytokine production .
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Publication Date: 2017-09-28 PubMed ID: 29034249PubMed Central: PMC5624997DOI: 10.3389/fvets.2017.00160Google Scholar: Lookup
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  • Journal Article

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 study investigates the effectiveness of misoprostol, usually used as a gastroprotectant in horses, in inhibiting the production of pro-inflammatory cytokines in equine (horse) leukocytes, which worsen diseases like sepsis and laminitis.

Research Objectives and Hypothesis

  • The researchers aimed to explore a novel method to control cytokine production, which involved increasing intracellular cyclic AMP levels.
  • Human leukocytes can boost the production of intracellular cAMP when E-prostanoid (EP) receptors 2 and 4 are activated. Misoprostol can trigger these receptors and was therefore tested for its efficacy in reducing pro-inflammatory cytokine production in equine leukocytes.
  • The study hypothesized that the use of misoprostol would inhibit pro-inflammatory cytokine production in lipopolysaccharide (LPS)—a compound that induces inflammation—stimulated equine leukocytes.

Methodology

  • To test their hypothesis, they used leukocyte-rich plasma (LRP) collected from 12 health adult horses to simulate LPS-mediated inflammatory signaling.
  • The collected LRP was exposed to varied concentrations of misoprostol before or after LPS stimulation.
  • The researchers evaluated the cytokines present in the LRP post-treatment via a bead-based immune-assay to observe any statistical differences.

Findings

  • Findings indicated that treating with misoprostol, both before and after introducing LPS, inhibited TNFα and IL-6 protein production, but had no effect on IL-8 protein.
  • The study also found that misoprostol pretreatment led to increased IL-1β protein synthesis following 6 hours of LPS stimulation, while posttreatment led to inhibition of IL-1β protein production after 24 hours.
  • At the mRNA level, misoprostol both pre- and post-treatment, inhibited LPS-induced TNFα, IL-1β, and IL-6 mRNA production but did not affect IL-8 mRNA.

Conclusion

  • The results demonstrated that misoprostol could produce anti-inflammatory effects on equine leukocytes, but there were varying effects at the mRNA and the protein levels which were specific to each cytokine and dependent on the timing of administration.
  • This pattern suggests that misoprostol’s inhibition effects on equine cytokines could be complex and requires further investigation to solidify its potential application as a therapeutic for equine inflammatory diseases.

Cite This Article

APA
Martin EM, Messenger KM, Sheats MK, Jones SL. (2017). Misoprostol Inhibits Lipopolysaccharide-Induced Pro-inflammatory Cytokine Production by Equine Leukocytes. Front Vet Sci, 4, 160. https://doi.org/10.3389/fvets.2017.00160

Publication

Frontiers in veterinary science
ISSN: 2297-1769
NlmUniqueID: 101666658
Country: Switzerland
Language: English
Volume: 4
Pages: 160
PII: 160

Researcher Affiliations

Martin, Emily Medlin
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
Messenger, Kristen M
  • Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
  • Comparative Medicine Institute, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
Sheats, Mary Katherine
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
  • Comparative Medicine Institute, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
Jones, Samuel L
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
  • Comparative Medicine Institute, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.

Grant Funding

  • K01 OD015136 / NIH HHS

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