interleukin-8 and butaprost

Topics: Alprostadil; Animals; Cattle; Cells, Cultured; Cyclooxygenase 2; Dinoprostone; Endometrium; Epithelial Cells; Female; Gene Expression Regulation; Intercellular Signaling Peptides and Proteins; Interleukin-8; MAP Kinase Signaling System; Prostaglandin Antagonists; Receptors, Prostaglandin E, EP2 Subtype; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A; Xanthones

Numerous epidemiological studies have linked exposure to particulate matter (PM) air pollution with acute respiratory infection and chronic respiratory and cardiovascular diseases. We have previously shown that soluble nickel (Ni), a common component of PM, alters the release of CXC chemokines from cultured human lung fibroblasts (HLF) in response to microbial stimuli via a pathway dependent on disrupted prostaglandin (PG)E2 signaling. The current study sought to identify the molecular events underlying Ni-induced alterations in PGE2 signaling and its effects on IL-8 production. PGE2 synergistically enhances Ni-induced IL-8 release from HLF in a concentration-dependent manner. The effects of PGE2 were mimicked by butaprost and PGE1-alcohol and inhibited with antagonists AH6809 and L-161,982, indicating PGE2 signals via PGE2 receptors 2 and 4. PGE2 and forskolin stimulated cAMP, but it was only in the presence of Ni-induced hypoxia-inducible factor 1, α subunit (HIF1A) that these agents stimulated IL-8 release. The Ni-induced HIF1A DNA binding was enhanced by PGE2 and mediated, in part, by activation of p38 MAPK. Negation of cAMP-response element binding protein 1 or HIF1A using short interfering RNA blocked the synergistic interactions between Ni and PGE2. The results of the current study provide novel information on the ability of atmospheric hypoxia-mimetic metals to disrupt the release of immune-modulating chemokines by HLF in response to PGE2. Moreover, in the presence of HIF1A, cAMP-mediated signaling pathways may be altered to exacerbate inflammatory-like processes in lung tissue, imparting a susceptibility of PM-exposed populations to adverse respiratory health effects.

Topics: Alprostadil; Biomimetics; Cells, Cultured; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Dinoprostone; Drug Synergism; Fibroblasts; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Interleukin-8; Lung; Nickel; p38 Mitogen-Activated Protein Kinases; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; Xanthones

Reports indicate that prostaglandin (PG)E(2) markedly enhances antigen-mediated degranulation in mouse bone marrow-derived mast cells (BMMCs) but not in human mast cells (HuMCs). We have examined the underlying mechanism(s) for this disparity in HuMCs derived from the peripheral blood of multiple donors in addition to mouse BMMCs. HuMCs from half of these donors failed to respond to PGE(2) and the PGE(2) EP3 receptor agonist, sulprostone. However, HuMCs from the remaining donors and the LAD2 human MC line responded to PGE(2) and sulprostone with marked enhancement of antigen-mediated degranulation and IL-8 production in a similar manner to that observed in mouse BMMCs. The EP2 agonist, butaprost, failed to modulate antigen-mediated responses in any type of MCs. These distinct phenotypes could not be explained by differences in EP2 or EP3 expression nor by differences in the ability of PGE(2) to elevate levels of cAMP, a signal recognized to down-regulate mast cell activation. Moreover, both responder and non-responder HuMC populations exhibited similar activation of phosphatidylinositol 3-kinase, and MAP kinases. However, translocation of PLCγ(1) to the cell membrane and the associated calcium signal were enhanced only in the responder HuMC population indicating that the link between EP3 and PLCγ is impaired in the non-responder HuMCs.. These data provide a cautionary note for the translating of observations in the mouse to human mast cell-dependent disorders, but may also provide a basis for examining the effects of co-activating receptors in patients susceptible to allergic conditions.

Topics: Alprostadil; Animals; Cell Degranulation; Cell Line; Dinoprostone; Humans; Interleukin-8; Mast Cells; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases; Phospholipase C gamma; Protein Transport; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP3 Subtype; Signal Transduction; Species Specificity