Prostaglandin e 2 enhances interleukin-8 production via ep4 receptor in human pulmonary microvascular endothelial cells

Hiromichi Aso, Satoru Ito, Akemi Mori, Masataka Morioka, Nobukazu Suganuma, Masashi Kondo, Kazuyoshi Imaizumi, Yoshinori Hasegawa

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Prostaglandin E 2 (PGE 2) is a bioactive prostanoid implicated in the inflammatory processes of acute lung injury/acute respiratory distress syndrome. This study investigated whether PGE2 can induce production of interleukin (IL)-8, the major chemokine for neutrophil activation, from human pulmonary microvascular endothelial cells (HPMVECs). PGE 2 significantly enhanced IL-8 protein production with increases in IL-8 mRNA expression and intracellular cAMP levels. HPMVECs expressed only EP4 receptor mRNA. The PGE 2 effects were mimicked by a selective EP4 receptor agonist, ONO-AE1-329, and inhibited by a selective EP4 receptor antagonist, ONO-AE3-208, or a protein kinase A inhibitor, Rp-adenosine 3',5'-cyclic monophosphorothioate triethylamine salt. The specific agonist for EP1, EP2, or EP3 receptor did not induce IL-8 production. PGE 2-induced IL-8 production was accompanied by p38 phosphorylation and was significantly inhibited by a p38 inhibitor, SB-203580, but not by an ERK1/2 inhibitor, U-0126, or a JNK inhibitor, SP-600125. Additionally, PGE 2 increased cyclooxygenase-2 expression with no change in constitutive cyclooxygenase-1 expression, suggesting possible involvement of an autocrine or paracrine manner. In conclusion, PGE 2 enhances IL-8 production via EP4 receptor coupled to Gs protein in HPMVECs. Activation of the cAMP/protein kinase A pathway, followed by p38 activation, is essential for these mechanisms. Because neutrophils play a critical role in the inflammation of acute lung injury/acute respiratory distress syndrome, IL-8 released from the pulmonary microvasculature in response to PGE 2 may contribute to pathophysiology of this disease.

Original languageEnglish
Pages (from-to)266-273
Number of pages8
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number2
Publication statusPublished - 01-01-2012


All Science Journal Classification (ASJC) codes

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology (medical)

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