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IL‐1β/HMGB1 Complexes Promote The PGE 2 Biosynthesis Pathway in Synovial Fibroblasts
Author(s) -
Leclerc P.,
Wähämaa H.,
Idborg H.,
Jakobsson P. J.,
Harris H. E.,
Korotkova M.
Publication year - 2013
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1111/sji.12041
Subject(s) - proinflammatory cytokine , hmgb1 , chemistry , cytokine , prostanoid , prostaglandin e2 , inflammation , tlr4 , prostaglandin , prostaglandin e , mediator , microbiology and biotechnology , arthritis , prostaglandin e2 receptor , receptor , immunology , endocrinology , biology , biochemistry , agonist
PGE 2 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 PGE 2 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 ( HMGB 1) is known to induce inflammation both by direct interaction with TLR 4 and by enhancement of other proinflammatory molecules signalling, through complex formation. The high expression of extracellular HMGB 1 within the inflamed synovium, implies its pro‐arthritogenic role in RA . We aimed to investigate the effects of IL ‐1β/ HMGB 1 complexes on mPGES ‐1 and other enzymes of the PGE 2 pathway in synovial fibroblasts ( SF s) from patients with arthritis. Furthermore, we studied the effect of COX ‐2 inhibition and IL‐1RI antagonism on prostanoid and cytokine production by SF s. Stimulation of SFs with HMGB1 in complex with suboptimal amounts of IL‐1β significantly increased mPGES ‐1 and COX ‐2 expressions as well as PGE 2 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 PGE 2 and cytokine production, suggesting an effect mediated through IL‐1RI. IL ‐1β/ HMGB 1 complexes promote the induction of mPGES ‐1, COX‐2 and PGE 2 in SF. The amplification of the PGE 2 biosynthesis pathway by HMGB 1 might constitute an important pathogenic mechanism perpetuating inflammatory and destructive activities in rheumatoid arthritis.