interleukin-8 and adenosine-3--5--cyclic-phosphorothioate

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 PGE(2) 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 G(s) 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.

Topics: Acute Lung Injury; Anthracenes; Butadienes; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Endothelial Cells; Humans; Imidazoles; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Lung; MAP Kinase Signaling System; Methyl Ethers; Microvessels; Naphthalenes; Neutrophils; Nitriles; p38 Mitogen-Activated Protein Kinases; Phenylbutyrates; Pyridines; Receptors, Prostaglandin E, EP4 Subtype; Respiratory Distress Syndrome; RNA, Messenger; Thionucleotides

Bidirectional signalling, i.e. simultaneous signalling through a receptor as well as its cell surface-bound ligand has been identified for several members of the TNF and TNF receptor family members. Reverse signalling through the ligands offers the advantage of an immediate feed-back and a more precise fine tuning of biological responses. Little is known about the molecular nature of reverse signalling through the ligands. CD137 ligand, member of the TNF family is expressed on monocytes and induces activation, migration, prolongation of survival and proliferation of monocytes. Here we show that reverse signalling by CD137 ligand is mediated by protein tyrosine kinases, p38 mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1,2, MAP/ERK kinase (MEK), Phosphoinositide-3-kinase (PI3-K) and protein kinase A (PKA) but not by protein kinase C (PKC). This study also shows that reverse signalling relies on the same signal transduction molecules as signalling through classical receptors and is in its nature not different from it.

Topics: 4-1BB Ligand; Alkaloids; Androstadienes; Benzophenanthridines; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Extracellular Signal-Regulated MAP Kinases; Humans; Interleukin-8; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Monocytes; Phosphatidylinositol 3-Kinases; Phosphorylation; Phosphotyrosine; Protein Kinase C; Pyrazoles; Pyrimidines; Signal Transduction; Thionucleotides; Wortmannin