prostaglandin-d2 and Peritonitis

15-Deoxy-Δ. 15d-PGJ

Topics: Animals; CD36 Antigens; Gene Expression Regulation; Heme Oxygenase-1; Humans; Jurkat Cells; Macrophages; Mice; NF-E2-Related Factor 2; Peritonitis; Phagocytosis; Prostaglandin D2; RAW 264.7 Cells; Zymosan

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a crucial role in protection of cells from electrophile-induced toxicity through up-regulating phase II detoxifying enzymes and phase III transporters. We previously reported that oxidative stress induces up-regulation of interleukin-11 (IL-11), a member of the IL-6 family that ameliorates acetaminophen-induced liver toxicity. However, a role for IL-11 in protection of cells from electrophile-induced toxicity remains unclear. Here we show that an environmental electrophile, 1,2-naphthoquinone (1,2-NQ), but not 15d-prostaglandin J

Topics: Animals; Antineoplastic Agents; Cells, Cultured; Gene Expression Regulation; HEK293 Cells; Hep G2 Cells; Humans; Hydrogen Peroxide; Interleukin-11; Interleukin-11 Receptor alpha Subunit; Intestinal Diseases; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Naphthoquinones; NF-E2-Related Factor 2; Oxidants; Oxidative Stress; Peritonitis; Prostaglandin D2; Reactive Oxygen Species

15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, has physiological properties including pronounced anti-inflammatory activity, though it binds strongly to serum albumin. The use of solid lipid nanoparticles (SLN) can improve therapeutic properties increasing drug efficiency and availability. 15d-PGJ2-SLN was therefore developed and investigated in terms of its immunomodulatory potential. 15d-PGJ2-SLN and unloaded SLN were physicochemically characterized and experiments in vivo were performed. Animals were pretreated with 15d-PGJ2-SLN at concentrations of 3, 10 or 30 μg·kg-1 before inflammatory stimulus with carrageenan (Cg), lipopolysaccharide (LPS) or mBSA (immune response). Interleukins (IL-1β, IL-10 and IL-17) levels were also evaluated in exudates. The 15d-PGJ2-SLN system showed good colloidal parameters and encapsulation efficiency of 96%. The results showed that the formulation was stable for up to 120 days with low hemolytic effects. The 15d-PGJ2-SLN formulation was able to reduce neutrophil migration in three inflammation models tested using low concentrations of 15d-PGJ2. Additionally, 15d-PGJ2-SLN increased IL-10 levels and reduced IL-1β as well as IL-17 in peritoneal fluid. The new 15d-PGJ2-SLN formulation highlights perspectives of a potent anti-inflammatory system using low concentrations of 15d-PGJ2.

Topics: Animals; Anti-Inflammatory Agents; BALB 3T3 Cells; Carrageenan; Cell Survival; Gene Expression Regulation; Interleukins; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Nanoparticles; Neutrophil Infiltration; Particle Size; Peritonitis; Prostaglandin D2

The kinetic participation of macrophages is critical for inflammatory resolution and recovery from myocardial infarction (MI), particularly with respect to the transition from the M1 to the M2 phenotype; however, the underlying mechanisms are poorly understood. In this study, we found that the deletion of prostaglandin (PG) D2 receptor subtype 1 (DP1) in macrophages retarded M2 polarization, antiinflammatory cytokine production, and resolution in different inflammatory models, including the MI model. DP1 deletion up-regulated proinflammatory genes expression via JAK2/STAT1 signaling in macrophages, whereas its activation facilitated binding of the separated PKA regulatory IIα subunit (PRKAR2A) to the transmembrane domain of IFN-γ receptor, suppressed JAK2-STAT1 axis-mediated M1 polarization, and promoted resolution. PRKAR2A deficiency attenuated DP1 activation-mediated M2 polarization and resolution of inflammation. Collectively, PGD2-DP1 axis-induced M2 polarization facilitates resolution of inflammation through the PRKAR2A-mediated suppression of JAK2/STAT1 signaling. These observations indicate that macrophage DP1 activation represents a promising strategy in the management of inflammation-associated diseases, including post-MI healing.

Topics: Animals; Cecum; Cell Polarity; Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; Disease Models, Animal; Female; Gene Deletion; Hydantoins; Inflammation; Janus Kinase 2; Ligation; Macrophages; Mice, Inbred C57BL; Myocardial Infarction; Myocardial Ischemia; Peritonitis; Prostaglandin D2; Protein Binding; Protein Subunits; Punctures; Receptors, Immunologic; Receptors, Interferon; Receptors, Prostaglandin; Signal Transduction; STAT1 Transcription Factor; Wound Healing; Zymosan

Extensive evidence indicates that nutrient excess associated with obesity and type 2 diabetes activates innate immune responses that lead to chronic, sterile low-grade inflammation, and obese and diabetic humans also have deficits in wound healing and increased susceptibility to infections. Nevertheless, the mechanisms that sustain unresolved inflammation during obesity remain unclear. In this study, we report that saturated free fatty acids that are elevated in obesity alter resolution of acute sterile inflammation by promoting neutrophil survival and decreasing macrophage phagocytosis. Using a targeted mass spectrometry-based lipidomics approach, we found that in db/db mice, PGE2/D2 levels were elevated in inflammatory exudates during the development of acute peritonitis. Moreover, in isolated macrophages, palmitic acid stimulated cyclooxygenase-2 induction and prostanoid production. Defects in macrophage phagocytosis induced by palmitic acid were mimicked by PGE2 and PGD2 and were reversed by cyclooxygenase inhibition or prostanoid receptor antagonism. Macrophages isolated from obese-diabetic mice expressed prostanoid receptors, EP2 and DP1, and contained significantly higher levels of downstream effector, cAMP, compared with wild-type mice. Therapeutic administration of EP2/DP1 dual receptor antagonist, AH6809, decreased neutrophil accumulation in the peritoneum of db/db mice, as well as the accumulation of apoptotic cells in the thymus. Taken together, these studies provide new insights into the mechanisms underlying altered innate immune responses in obesity and suggest that targeting specific prostanoid receptors may represent a novel strategy for resolving inflammation and restoring phagocyte defects in obese and diabetic individuals.

Topics: Animals; Apoptosis; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Fatty Acids; Humans; Inflammation; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neutrophils; Obesity; Palmitic Acid; Peritonitis; Phagocytosis; Prostaglandin D2; Receptors, Prostaglandin; Receptors, Prostaglandin E, EP2 Subtype; Xanthones

Mechanisms underlying delays in resolution programs of inflammation are of interest for many diseases. Here, we addressed delayed resolution of inflammation and identified specific microRNA (miR)-metabolipidomic signatures. Delayed resolution initiated by high-dose challenges decreased miR-219-5p expression along with increased leukotriene B(4) (5-fold) and decreased (~3-fold) specialized pro-resolving mediators, e.g. protectin D1. Resolvin (Rv)E1 and RvD1 (1 nM) reduced miR-219-5p in human macrophages, not shared by RvD2 or PD1. Since mature miR-219-5p is produced from pre-miRs miR-219-1 and miR-219-2, we co-expressed in human macrophages a 5-lipoxygenase (LOX) 3'UTR-luciferase reporter vector together with either miR-219-1 or miR-219-2. Only miR-219-2 reduced luciferase activity. Apoptotic neutrophils administered into inflamed exudates in vivo increased miR-219-2-3p expression and PD1/NPD1 levels as well as decreased leukotriene B(4). These results demonstrate that delayed resolution undermines endogenous resolution programs, altering miR-219-2 expression, increasing pro-inflammatory mediators and compromising SPM production that contribute to failed catabasis and homeostasis.

Topics: 3' Untranslated Regions; Acute Disease; Animals; Apoptosis; Arachidonate 5-Lipoxygenase; Cells, Cultured; Dinoprostone; Exudates and Transudates; Gene Expression; Humans; Inflammation; Inflammation Mediators; Leukotriene B4; Lipid Metabolism; Macrophages; Male; Mice; MicroRNAs; Neutrophils; Peritonitis; Prostaglandin D2; RNA Interference; Zymosan

The PPAR-γ agonist 15d-PGJ₂ is a potent anti-inflammatory agent but only at high doses. To improve the efficiency of 15d-PGJ₂, we used poly(D,L-lactide-co-glycolide) nanocapsules to encapsulate it, and function as a drug carrier system. The effects of these loaded nanocapsules (15d-PGJ₂-NC) on inflammation induced by different stimuli were compared with those of free 15d-PGJ₂.. Mice were pretreated (s.c.) with either 15d-PGJ₂-NC or unloaded 15d-PGJ₂ (3, 10 or 30 µg·kg⁻¹), before induction of an inflammatory response by i.p. injection of either endotoxin (LPS), carrageenan (Cg) or mBSA (immune response).. The 15d-PGJ₂-NC complex did not display changes in physico-chemical parameters or drug association efficiency over time, and was stable for up to 60 days of storage. Neutrophil migration induced by i.p. administration of LPS, Cg or mBSA was inhibited by 15d-PGJ₂-NC, but not by unloaded 15d-PGJ₂. In the Cg model, 15d-PGJ₂-NC markedly inhibited serum levels of the pro-inflammatory cytokines TNF-α, IL-1β and IL-12p70. Importantly, 15d-PGJ₂-NC released high amounts of 15d-PGJ₂, reaching a peak between 2 and 8 h after administration. 15d-PGJ ₂ was detected in mouse serum after 24 h, indicating sustained release from the carrier. When the same concentration of unloaded 15d-PGJ₂ was administered, only small amounts of 15d-PGJ₂ were found in the serum after a few hours.. The present findings clearly indicate the potential of the novel anti-inflammatory 15d-PGJ₂ carrier formulation, administered systemically. The formulation enables the use of a much smaller drug dose, and is significantly more effective compared with unloaded 15d-PGJ₂.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biocompatible Materials; Carrageenan; Cytokines; Drug Carriers; Hemoglobins; Immunization; Inflammation; Lactic Acid; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Nanocapsules; Neutrophil Infiltration; Neutrophils; Particle Size; Peritonitis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Prostaglandin D2; Serum Albumin, Bovine

Matrix metalloproteinase-9 (MMP-9)/gelatinase B plays an important role in neutrophil infiltration during inflammation and cyclooxygenases (COX-1 and COX-2) and their products are important regulators of inflammation. Recently, we reported that a genetic lack of MMP-9 impairs neutrophil infiltration during early zymosan-induced peritonitis but at later stages (> 24 hr) neutrophils persist in the peritoneal cavity. Here we show that this is the result of impaired apoptosis of MMP-9(-/-)-derived leucocytes. As enhanced COX-1 expression was reported in MMP-9(-/-) mice, we evaluated the hypothesis that altered COX expression induced the above phenomenon as COX-dependent prostaglandins can act either anti-apoptotically (PGE(2)) or pro-apoptotically (PGD(2)). The current data demonstrate that messenger RNA and protein expression of both COX isoforms and their activities are increased in MMP-9(-/-) mice during late peritonitis. Application of selective COX inhibitors revealed enhanced COX-1-dependent PGE(2) production and impaired COX-2-dependent PGD(2) synthesis in MMP-9(-/-) mice. Most importantly, inhibition of COX-1 abolished prolonged neutrophil accumulation in the peritoneal cavity of MMP-9(-/-) mice and increased apoptosis of inflammatory leucocytes. Similarly, weaker apoptosis of MMP-9(-/-) bone marrow neutrophils treated in vitro with zymosan was reversed by COX-1 inhibition. In conclusion, enhanced COX-1 expression is responsible for persistent neutrophil presence in the peritoneum of MMP-9(-/-) mice because of increased synthesis of anti-apoptotic PGE(2). In non-transgenic mice, however, inflammatory leucocytes die apoptotically in the late stages of peritonitis as a result of COX-2-dependent PGD(2) activity. Overall, we show a dependence of COX expression on the presence of MMP-9.

Topics: Animals; Apoptosis; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprostone; Male; Matrix Metalloproteinase 9; Membrane Proteins; Mice; Mice, Knockout; Neutrophil Infiltration; Neutrophils; Peritonitis; Prostaglandin D2; Pyrazoles; Thiophenes; Zymosan

The histamine H4 receptor is widely expressed in cells of immune origin and has been shown to play a role in a variety of inflammatory processes mediated by histamine. In this report, we describe the in vitro and in vivo anti-inflammatory properties of a potent histamine H4 receptor antagonist, A-940894 (4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine).. We have analysed the pharmacological profile of A-940894 at mouse native, rat recombinant and human recombinant and native, histamine H4 receptors by radioligand binding, calcium mobilization, mast cell shape change, eosinophil chemotaxis assays and in the mouse model of zymosan-induced peritonitis.. A-940894 potently binds to both human and rat histamine H4 receptors and exhibits considerably lower affinity for the human histamine H1, H2 or H3 receptors. It potently blocked histamine-evoked calcium mobilization in the fluorometric imaging plate reader assays and inhibited histamine-induced shape change of mouse bone marrow-derived mast cells and chemotaxis of human eosinophils in vitro. In a mouse mast cell-dependent model of zymosan-induced peritonitis, A-940894 significantly blocked neutrophil influx and reduced intraperitoneal prostaglandin D2 levels. Finally, A-940894 has good pharmacokinetic properties, including half-life and oral bioavailability in rats and mice.. These data suggest that A-940894 is a potent and selective histamine H4 receptor antagonist with pharmacokinetic properties suitable for long-term in vivo testing and could serve as a useful tool for the further characterization of histamine H4 receptor pharmacology.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Binding, Competitive; Calcium; Cell Shape; Chemotaxis; Eosinophils; Female; Histamine; Humans; Male; Mast Cells; Mice; Mice, Inbred BALB C; Peritonitis; Piperazines; Prostaglandin D2; Pyrimidines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Recombinant Proteins; RNA, Messenger; Zymosan

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Proliferation; Chronic Disease; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation; Lipid Metabolism; Lipids; Lymphocytes; Mice; Models, Biological; Peritonitis; Prostaglandin D2; Time Factors

15-Deoxy-delta(12,14)-prostaglandin J2 (dPGJ2) is a bioactive metabolite of the J2 series that has been identified as a ligand for peroxisome proliferator-activated receptor gamma (PPARgamma). Because PPARgamma is highly expressed in macrophages obtained from stimulant-elicited peritonitis, but not in resident peritoneal macrophages, the effect of dPGJ2 was tested on innate functions of macrophages. dPGJ2 inhibited adhesion and phagocytosis of Escherichia coli. Inhibition of these functions by dPGJ2 was not mediated via the adhesion molecule Mac-1. In addition, dPGJ2 inhibited chemotaxis toward zymosan-activated serum and it also inhibited the production of superoxide anion when macrophages were stimulated with phorbol 12-myristate 13-acetate (PMA) or opsonized zymosan (OPZ), but not lipopolysaccharide. Similarly, dPGJ2 inhibited the production of hydrogen peroxide when macrophages were stimulated with either PMA or OPZ. These studies suggest that dPGJ2 may be a negative regulator of macrophage functions.

Topics: Animals; Cell Adhesion; Chemotaxis; Escherichia coli; Hydrogen Peroxide; Inflammation; Ligands; Lipopolysaccharides; Macrophage-1 Antigen; Macrophages, Peritoneal; Male; Oxidative Stress; Peritonitis; Phagocytosis; Prostaglandin D2; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Superoxides; Tetradecanoylphorbol Acetate; Transcription Factors; Zymosan