title: IL-1β/HMGB1 complexes promote The PGE2 biosynthesis pathway in synovial fibroblasts.
abstract: PGE2 is a potent lipid mediator of pain and oedema found elevated in RA. Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal enzyme of the PGE2 pathway inducible by proinflammatory cytokines. mPGES-1 is markedly upregulated in RA synovial tissue despite antirheumatic treatments, suggesting that multiple inflammatory stimuli contribute to its induction. High-mobility group box chromosomal protein 1 (HMGB1) is known to induce inflammation both by direct interaction with TLR4 and by enhancement of other proinflammatory molecules signalling, through complex formation. The high expression of extracellular HMGB1 within the inflamed synovium, implies its pro-arthritogenic role in RA. We aimed to investigate the effects of IL-1β/HMGB1 complexes on mPGES-1 and other enzymes of the PGE2 pathway in synovial fibroblasts (SFs) from patients with arthritis. Furthermore, we studied the effect of COX-2 inhibition and IL-1RI antagonism on prostanoid and cytokine production by SFs. Stimulation of SFs with HMGB1 in complex with suboptimal amounts of IL-1β significantly increased mPGES-1 and COX-2 expressions as well as PGE2 production, as compared to treatment with HMGB1 or IL-1β alone. Furthermore, NS-398 reduced the production of IL-6 and IL-8, thus indicating that IL-1β/HMGB1 complexes modulate cytokine production in part through prostanoid synthesis. Treatment with IL-1RA completely abolished the induced PGE2 and cytokine production, suggesting an effect mediated through IL-1RI. IL-1β/HMGB1 complexes promote the induction of mPGES-1, COX-2 and PGE2 in SF. The amplification of the PGE2 biosynthesis pathway by HMGB1 might constitute an important pathogenic mechanism perpetuating inflammatory and destructive activities in rheumatoid arthritis.
authors.affiliation: Rheumatology Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Leclerc
authors.forename: H
authors.initials: H
authors.lastname: Wähämaa
authors.forename: H
authors.initials: H
authors.lastname: Idborg
authors.forename: P J
authors.initials: PJ
authors.lastname: Jakobsson
authors.forename: H E
authors.initials: HE
authors.lastname: Harris
authors.forename: M
authors.initials: M
authors.lastname: Korotkova
mesh_terms: D001168:Arthritis / Q000378:metabolism / Q000473:pathology; D053898:Biosynthetic Pathways / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis*; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D024243:HMGB1 Protein / Q000494:pharmacology*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D000071876:Prostaglandin-E Synthases; D013449:Sulfonamides / Q000494:pharmacology; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology
chemical_list: D018925:Chemokines; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D024243:HMGB1 Protein; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone