butaprost and Inflammation

Down-regulation of the E-prostanoid (EP)2 receptor has been reported in aspirin exacerbated respiratory disease (AERD). We aimed to evaluate the expression and activation of EP receptors in AERD and their role in prostaglandin (PG) E2 signalling.. Samples were obtained from nasal mucosa of control subjects (NM-C, n=7) and from nasal polyps of AERD patients (NP-AERD, n=7). Expression of EP1-4 was assessed at baseline. Fibroblasts were stimulated with receptor agonists to measure cAMP levels, cell proliferation and granulocyte-macrophage colony-stimulating factor (GM-CSF) release.. NM-C and NP-AERD samples and fibroblasts expressed EP2, EP3 and EP4 at baseline. Lower expression of EP2 and higher expression of EP4 was observed in NP-AERD compared with NM-C. Stimulation with PGE2 and butaprost caused a higher increase in cAMP in NM-C than in NP-AERD. On the contrary, CAY10598 produced a higher production of cAMP in NP-AERD compared with NM-C. The anti-proliferative effect of PGE2 and butaprost was lower in NP-AERD than in NM-C fibroblasts. Similarly, the capacity of PGE2 and butaprost to inhibit GM-CSF release was lower in NP-AERD than in NM-C.. The altered expression of EP2 in AERD may contribute to reduce the capacity of PGE2 to mediate anti-proliferative and anti-inflammatory effects.

Topics: Alprostadil; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cell Proliferation; Cyclic AMP; Dinoprostone; Disease Progression; Down-Regulation; Female; Fibroblasts; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Inflammation; Male; Middle Aged; Nasal Mucosa; Nasal Polyps; Receptors, Prostaglandin E; Respiratory Tract Diseases; Signal Transduction

Prostaglandin (PG) E2 (PGE(2)) plays a central role in the regulation of smooth muscle contractions. Classically, PGE(2) stimulates contractions via EP1 and EP3 receptors, whereas EP2 and EP4 maintain quiescence. Labor involves a change from myometrial quiescence to contractions with a shift from anti- to proinflammatory pathways. EP2, a Gαs-coupled receptor, is known to mediate its actions via cAMP signaling. However, we have recently shown that EP2 also activates the proinflammatory PG G/H synthase-2 (PGHS-2). Here, we identify the mechanism underlying the ability of EP2 to maintain uterine quiescence and activate a proinflammatory/prolabor response in term-pregnant human myometrium. Human myometrial biopsies for in vivo and in vitro studies were taken at cesarean section at term, before or after the onset of labor. Activation of EP2 increased intracellular levels of cAMP and reduced contractility. Contrastingly, EP2 stimulation increased levels of PGHS-2, membrane-associated PGE synthase-1, and PGE(2). This was entirely dependent on EP2-mediated activation of calcium signaling. Both calcium signaling and up-regulation of PGHS-2 were insensitive to the Gαi inhibitor pertussis toxin but inhibited by small interfering RNA knockdown of Gαq/11. There were no differences in EP2 mRNA or protein levels between upper or lower segment myometrium or between pre- and postlabor myometrium. However, in myocytes taken after the onset of labor, cAMP signaling was markedly attenuated, whereas activation of calcium and PGHS-2 was preserved. Overall, the dual coupling of EP2 to Gαs-cAMP and Gαq/11-calcium pathways underlies its ability to mediate contrasting functions in term pregnancy and the "switching" to a prolabor receptor.

Topics: Alprostadil; Calcium; Dinoprostone; Female; Humans; Inflammation; Muscle Relaxation; Myometrium; Pregnancy; Receptors, Prostaglandin E, EP2 Subtype; Signal Transduction; Up-Regulation; Uterine Contraction

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

Among prostaglandins (PGs), PGE2 is abundantly expressed in various malignancies and is probably one of many factors promoting tumor growth by inhibiting tumor immune surveillance. In the current study, we report on a novel mechanism by which PGE2 inhibits in vitro natural killer-dendritic cell (NK-DC) crosstalk and thereby innate and adaptive immune responses via its effect on NK-DC crosstalk. The presence of PGE2 during IFN-γ/membrane fraction of Klebsiella pneumoniae DC maturation inhibits the production of chemokines (CCL5, CCL19, and CXCL10) and cytokines (IL-12 and IL-18), which is cAMP-dependent and imprinted during DC maturation. As a consequence, these DCs fail to attract NK cells and show a decreased capacity to trigger NK cell IFN-γ production, which in turn leads to reduced T-helper 1 polarization. In addition, the presence of PGE2 during DC maturation impairs DC-mediated augmentation of NK-cell cytotoxicity. Opposed to their inhibitory effects on peripheral blood-derived NK cells, PGE2 matured DCs induce IL-22 secretion of inflammation constraining NKp44(+) NK cells present in mucosa-associated lymphoid tissue. The inhibition of NK-DC interaction is a novel regulatory property of PGE2 that is of possible relevance in dampening immune responses in vivo.

Topics: Alprostadil; Bucladesine; Cell Differentiation; Cell Movement; Cells, Cultured; Chemokines; Coculture Techniques; Cytokines; Cytotoxicity, Immunologic; Dendritic Cells; Dinoprostone; Down-Regulation; Gene Expression Regulation; Humans; Immunosuppression Therapy; Inflammation; Interferon-gamma; Killer Cells, Natural; Klebsiella pneumoniae; Misoprostol; Palatine Tonsil; T-Lymphocytes, Helper-Inducer

The purpose of the study was to investigate the role of EP1 receptors in intraocular inflammation and to determine possible interplay between EP1, EP2 and EP4 receptors. The eyes of separate groups of EP1 receptor knockout and wild type mice were: 1) treated topically with prostaglandin E2 (PGE2) or the EP2 receptor selective agonist, butaprost; 2) given intravitreal injection of LPS; or 3) paracentesis performed. Another group of knockout mice were pretreated topically with an EP4 receptor selective antagonist prior to paracentesis or LPS treatment. Results demonstrated a significant increase (50% or more) in the protein levels of aqueous humor of the EP1 knockout mice in response to PGE2, paracentesis or LPS. The leukocyte infiltration in the aqueous humor of the knockout mice was 47% higher when compared with that in the wild type controls in response to LPS injection. No significant change was observed in the protein levels in response to butaprost. Pretreating the knockout mice with an EP4 receptor antagonist prior to paracentesis and LPS treatment substantially reduced the aqueous humor protein levels. Also, the leukocyte count in the aqueous humor of the knockout mice in response to LPS was reduced 4 fold after pretreatment with EP4 receptor antagonist when compared with the findings in knockout mice receiving LPS only. We concluded that EP1 receptor has no modulatory effect on EP2 receptors but there is definitely cross-talk between EP1 and EP4 receptors.

Topics: Alprostadil; Animals; Aqueous Humor; Blood-Aqueous Barrier; Dinoprostone; Eye Proteins; Inflammation; Leukocyte Count; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Paracentesis; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype

Interleukin-23, a recently described cytokine produced by activated antigen-presenting cells, including dendritic cells, is a p19/p40 heterodimer. The p40 subunit is shared with IL-12, the major Th1-driving cytokine, while p19 is distantly related to IL-12 p35. IL-23 has pro-inflammatory actions, inducing IL-17 secretion from activated CD4+ T cells, and stimulating the proliferation of memory CD4+ T cells. Here, we examined the effects of PGE2, a well-known immunomodulator, on the production of IL-23 by bone marrow- derived dendritic cells (BM-DCs). Our results indicate that PGE2 increases the production of functional IL-23 from immature BM-DCs in a time- and dose-dependent manner. PGE2 induces both the expression of p19 and p40, without affecting p35 expression. The effect of PGE2 is mediated through the specific receptors EP2/4 and is mimicked by cAMP-inducing agents, such as forskolin and dbcAMP. Although PGE2 also induces IL-1beta and IL-6 expression in non-stimulated DCs, the stimulatory effect of PGE2 on IL-23 production is not mediated through IL-1beta or IL-6. GM-CSF, the pro-inflammatory cytokine required for the generation of BM-DCs, amplifies the IL-23 inducing activity of PGE2 in a synergistic manner. Recent studies described both pro- and anti-inflammatory effects of PGE2, and our results suggest an additional mechanism for its pro-inflammatory role, particularly significant for autoimmune diseases, such as rheumatoid arthritis.

Topics: Alprostadil; Animals; Arthritis; Bone Marrow Cells; Bucladesine; CD4-Positive T-Lymphocytes; Cell Line, Tumor; Cells, Cultured; Colforsin; Culture Media, Conditioned; Cyclic AMP; Dendritic Cells; Dinoprostone; Gene Expression Regulation; Inflammation; Interleukin-12; Interleukin-12 Subunit p35; Interleukin-12 Subunit p40; Interleukin-17; Interleukin-23; Interleukin-23 Subunit p19; Interleukins; Lipopolysaccharides; Male; Mice; Misoprostol; Plasmacytoma; Prostaglandin Antagonists; Protein Subunits; Receptors, Cell Surface; Second Messenger Systems; Specific Pathogen-Free Organisms; Toll-Like Receptor 2; Toll-Like Receptor 4

Topics: Alprostadil; Animals; Bradykinin; Capillary Permeability; Dinoprostone; Drug Synergism; Inflammation; Rabbits; Receptors, Prostaglandin; Receptors, Prostaglandin E; Skin; Vasodilation