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Molecular Medicine

, Volume 14, Issue 7–8, pp 422–428 | Cite as

Lysophosphatidic Acid Inhibits Bacterial Endotoxin-Induced Pro-Inflammatory Response: Potential Anti-Inflammatory Signaling Pathways

  • Hongkuan Fan
  • Basilia Zingarelli
  • Vashaunta Harris
  • George E. Tempel
  • Perry V. Halushka
  • James A. Cook
Research Article

Abstract

Previous studies have demonstrated that heterotrimeric guanine nucleotide-binding regulatory (Gi) protein-deficient mice exhibit augmented inflammatory responses to lipopolysaccharide (LPS). These findings suggest that Gi protein agonists will suppress LPS-induced inflammatory gene expression. Lysophosphatidic acid (LPA) activates G protein-coupled receptors leading to Gi protein activation. We hypothesized that LPA will inhibit LPS-induced inflammatory responses through activation of Gi-coupled anti-inflammatory signaling pathways. We examined the anti-inflammatory effect of LPA on LPS responses both in vivo and in vitro in CD-1 mice. The mice were injected intravenously with LPA (10 mg/kg) followed by intraperitoneal injection of LPS (75 mg/kg for survival and 25 mg/kg for other studies). LPA significantly increased the mice survival to endotoxemia (P < 0.05). LPA injection reduced LPS-induced plasma TNF-α production (69 ± 6%, P < 0.05) and myeloperoxidase (MPO) activity in lung (33 ± 9%, P < 0.05) as compared to vehicle injection. LPS-induced plasma IL-6 was unchanged by LPA. In vitro studies with peritoneal macrophages paralleled results from in vivo studies. LPA (1 and 10 µM) significantly inhibited LPS-induced TNFα production (61 ± 9% and 72 ± 9%, respectively, P < 0.05) but not IL-6. We further demonstrated that the anti-inflammatory effect of LPA was reversed by ERK 1/2 and phosphatase inhibitors, suggesting that ERK 1/2 pathway and serine/threonine phosphatases are involved. Inhibition of phosphatidylinositol 3 (PI3) kinase signaling pathways also partially reversed the LPA anti-inflammatory response. However, LPA did not alter NFκB and peroxisome proliferator-activated receptor γ (PPARγ) activation. Inhibitors of PPARγ did not alter LPA-induced inhibition of LPS signaling. These studies demonstrate that LPA has significant anti-inflammatory activities involving activation of ERK 1/2, serine/threonine phosphatases, and PI3 kinase signaling pathways.

Notes

Acknowledgments

This work was supported by NIH GM27673 and NIH GM67202.

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Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Hongkuan Fan
    • 1
  • Basilia Zingarelli
    • 2
  • Vashaunta Harris
    • 1
  • George E. Tempel
    • 1
  • Perry V. Halushka
    • 3
  • James A. Cook
    • 1
  1. 1.Department of NeurosciencesMedical University of South CarolinaCharlestonUSA
  2. 2.Division of Critical Care MedicineCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  3. 3.Medicine, and PharmacologyMedical University of South CarolinaCharlestonUSA

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