The Synovial Prostaglandin System in Chronic Inflammatory Arthritis: Differential Effects of Steroidal and Nonsteroidal Anti‐inflammatory Drugs

308

115

15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) has been identified as an endogenous ligand for PPARγ, inducing adipogenesis in vitro. Additional roles for this molecule in the propagation and resolution of inflammation, ligation of NF-κB, 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 PPARγ-dependent adipocyte activation and is unaltered in clinical settings in which PPARγ activation has been implicated

Section: Discussionmentioning

confidence: 99%

Biosynthesis of 15-deoxy-Δ12,14-PGJ2 and the ligation of PPARγ

Bell-Parikh¹,

Ide²,

Lawson³

et al. 2003

308

115

“…Prostaglandins are important lipid mediators that are produced at elevated levels in inflamed tissues including rheumatoid synovium (1,2). PGE 2 and PGI 2 likely contribute to synovial inflammation by increasing local blood flow and potentiating the effects of mediators such as bradykinin and IL-1 that induce vasopermeability (reviewed in reference 3).…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis.

Anderson¹,

Hauser²,

McGarity³

et al. 1996

533

319

Prostaglandins formed by the cyclooxygenase (COX) enzymes are important mediators of inflammation in arthritis. The contribution of the inducible COX-2 enzyme to inflammation in rat adjuvant arthritis was evaluated by characterization of COX-2 expression in normal and arthritic paws and by pharmacological inhibition of COX-2 activity. The injection of adjuvant induced a marked edema of the hind footpads with coincident local production of PGE 2 . PG production was associated with upregulation of COX-2 mRNA and protein in the affected paws. In contrast, the level of COX-1 mRNA was unaffected by adjuvant injection. TNF-␣ and IL-6 mRNAs were also increased in the inflamed paws as was IL-6 protein in the serum. Therapeutic administration of a selective COX-2 inhibitor, SC-58125, rapidly reversed paw edema and reduced the level of PGE 2 in paw tissue to baseline. Interestingly, treatment with the COX-2 inhibitor also reduced the expression of COX-2 mRNA and protein in the paw. Serum IL-6 and paw IL-6 mRNA levels were also reduced to near normal levels by SC-58125. Furthermore, inhibition of COX-2 resulted in a reduction of the inflammatory cell infiltrate and decreased inflammation of the synovium. Notably, the antiinflammatory effects of SC-58125 were indistinguishable from the effects observed for indomethacin. These results suggest that COX-2 plays a prominent role in the inflammation associated with adjuvant arthritis and that COX-2 derived PGs upregulate COX-2 and IL-6 expression at inflammatory sites. ( J. Clin. Invest. 1996. 97:2672-2679.)

“…Prostaglandins are produced at elevated levels in inflamed tissues including rheumatoid synovium (5,6). PGE 1 and PGE 2 contribute to synovial inflammation by increasing local blood flow and potentiating the effects of mediators such as bradykinin and IL-1 ␤ that induce vasopermeability (7).…”

Section: Introductionmentioning

confidence: 99%

Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide.

Amin¹,

Attur²,

Patel³

et al. 1997

356

285

Cartilage specimens from osteoarthritis (OA)-affected patients spontaneously released PGE 2 at 48 h in ex vivo culture at levels at least 50-fold higher than in normal cartilage and 18-fold higher than in normal cartilage ϩ cytokines ϩ endotoxin. The superinduction of PGE 2 production coincides with the upregulation of cyclooxygenase-2 (COX-2) in OA-affected cartilage. Production of both nitric oxide (NO) and PGE 2 by OA cartilage explants is regulated at the level of transcription and translation. Dexamethasone inhibited only the spontaneously released PGE 2 production, and not NO, in OA-affected cartilage. The NO synthase inhibitor H N G -monomethyl-L -arginine monoacetate inhibited OA cartilage NO production by Ͼ 90%, but augmented significantly (twofold) the spontaneous production of PGE 2 in the same explants. Similarly, addition of exogenous NO donors to OA cartilage significantly inhibited PGE 2 production. Cytokine ϩ endotoxin stimulation of OA explants increased PGE 2 production above the spontaneous release. Addition of L -NMMA further augmented cytokine-induced PGE 2 production by at least fourfold. Inhibition of PGE 2 by COX-2 inhibitors (dexamethasone or indomethacin) or addition of exogenous PGE 2 did not significantly affect the spontaneous NO production. These data indicate that human OA-affected cartilage in ex vivo conditions shows ( a ) superinduction of PGE 2 due to upregulation of COX-2, and ( b ) spontaneous release of NO that acts as an autacoid to attenuate the production of the COX-2 products such as PGE 2 . These studies, together with others, also suggest that PGE 2 may be differentially regulated in normal and OA-affected chondrocytes. ( J. Clin. Invest. 1997. 99:1231-1237.)