prostaglandin-d2 and Arthritis

Prostaglandin (PG)D2 has been shown to be an active agent in the resolution of experimentally induced inflammation. This study was undertaken to determine the presence of PGD2 in chronic joint effusions and to explore the potential contributions of dendritic cells (DC) and monocytes to the intra-articular synthesis of PGD2. Synovial fluid (SF) was obtained from patients with inflammatory arthritis and knee effusions. PGD2 and PGE2 were detected in SF by ultrahigh-performance tandem mass spectrometry. Cellular fractions in SF were separated by density-gradient centrifugation and flow cytometry. The expression of hematopoietic prostaglandin D-synthase (hPGDS) and PGE-synthase (PGES) mRNA was determined by RT-PCR. Both PGD2 and PGE2 were detected in blood and SF, with PGD2 being more abundant than PGE2 in SF. mRNA for hPGDS was more abundant in SF mDCs than SF monocytes (P < 0.01) or PB monocytes (P < 0.001). SF mDC expressed significantly more hPGDS than PGES. Expressions of PGD2 and hPGDS were inversely associated with serum C-reactive protein (P < 0.01) and erythrocyte sedimentation rate (P < 0.01). The findings suggest that synovial DCs may be an important source of hPGDS and that systemic disease activity may be influenced by actions of PGD2 in RA and other arthropathies.

Topics: Aged; Aged, 80 and over; Arthritis; Dendritic Cells; Dinoprostone; Female; Humans; Middle Aged; Prostaglandin D2; Prostaglandins D; Synovial Fluid; Tandem Mass Spectrometry

Prostaglandin D2(PGD2) is the most produced prostanoid in the CNS of mammals, and in behavioral experiments it has been implicated in the modulation of spinal nociception. In the present study we addressed the effects of spinal PGD2 on the discharge properties of nociceptive spinal cord neurons with input from the knee joint using extracellular recordings in vivo, both in normal rats and in rats with acute inflammation in the knee joint. Topical application of PGD2 to the spinal cord of normal rats did not influence responses to mechanical stimulation of the knee and ankle joint except at a high dose. Specific agonists at either the prostaglandin D2 receptor 1 (DP1) or the prostaglandin D2 receptor 2 (DP2) receptor had no effect on responses to mechanical stimulation of the normal knee. By contrast, in rats with inflamed knee joints either PGD2 or a DP1 receptor agonist decreased responses to mechanical stimulation of the inflamed knee and the non-inflamed ankle thus reducing established inflammation-evoked spinal hyperexcitability. Vice versa, spinal application of an antagonist at DP1 receptors increased responses to mechanical stimulation of the inflamed knee joint and the non-inflamed ankle joint suggesting that endogenous PGD2 attenuated central sensitization under inflammatory conditions, through activation of DP1 receptors. Spinal application of a DP2 receptor antagonist had no effect. The conclusion that spinal PGD2 attenuates spinal hyperexcitability under inflammatory conditions is further supported by the finding that spinal coapplication of PGD2 with prostaglandin E2 (PGE2) attenuated the PGE2-induced facilitation of responses to mechanical stimulation of the normal joint.

Topics: Action Potentials; Acute Disease; Afferent Pathways; Animals; Arthralgia; Arthritis; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Hindlimb; Nociceptors; Physical Stimulation; Posterior Horn Cells; Prostaglandin D2; Rats; Receptors, Immunologic; Receptors, Prostaglandin; Tarsus, Animal

15-deoxy-Delta12,14-PGJ2 (15d-PGJ2) has been identified as an endogenous ligand for PPARgamma, inducing adipogenesis in vitro. Additional roles for this molecule in the propagation and resolution of inflammation, ligation of NF-kappaB, and mediation of apoptosis have been proposed. However, quantitative, physiochemical evidence for the formation of 15d-PGJ2 in vivo is lacking. We report that 15d-PGJ2 is detectable using liquid chromatography-mass spectrometry-mass spectrometry at low picomolar concentrations in the medium of 3T3-L1 preadipocytes. However, despite induction of COX-2, production of PGs, including 15d-PGJ2, does not increase during adipocyte differentiation, a process unaltered by COX inhibition. 15d-PGJ2 is detectable as a minor product of COX-2 in human urine. However, its biosynthesis is unaltered during or after COX activation in vivo by LPS. Furthermore, the biosynthesis of 15d-PGJ2 is not augmented in the joint fluid of patients with arthritis, nor is its urinary excretion increased in patients with diabetes or obesity. 15d-PGJ2 is not the endogenous mediator of PPARgamma-dependent adipocyte activation and is unaltered in clinical settings in which PPARgamma activation has been implicated.

Topics: 3T3 Cells; Adipocytes; Aged; Aged, 80 and over; Animals; Arthritis; Cell Differentiation; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Female; Humans; Immunologic Factors; Isoenzymes; Ligands; Male; Mass Spectrometry; Membrane Proteins; Mice; Middle Aged; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Receptors, Cytoplasmic and Nuclear; Synovial Fluid; Transcription Factors

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and have a dominant regulatory role in adipocyte and monocyte differentiation. PPAR-gamma agonists are also negative regulators of macrophage activation and have modulatory effects on tumorigenesis. In this study we demonstrate that synovial tissue localized expression of PPAR-gamma in patients with rheumatoid arthritis (RA). We detected markedly enhanced expression of PPAR-gamma in macrophages, as well as modestly enhanced expression in the synovial lining layer, fibroblasts, and endothelial cells. Activation of the PPAR-gamma by 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and the synthetic PPAR-gamma ligand (troglitazone) induced RA synoviocyte apoptosis in vitro. Moreover, intraperitoneal administration of these PPAR-gamma ligands ameliorated adjuvant-induced arthritis with suppression of pannus formation and mononuclear cell infiltration in female Lewis rats. Anti-inflammatory effects of 15d-PGJ(2) were more potent than troglitazone. These findings suggest that PPAR-gamma may be an important immunoinflammatory mediator and its ligands, especially 15d-PGJ(2), may be useful in the treatment of RA.

Topics: Animals; Apoptosis; Arthritis; Arthritis, Experimental; Arthritis, Rheumatoid; Cells, Cultured; Chromans; Female; Humans; Ligands; Osteoarthritis; Prostaglandin D2; Rats; Rats, Inbred Lew; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Synovial Membrane; Thiazoles; Thiazolidinediones; Tissue Distribution; Transcription Factors; Troglitazone