Open AccessInterleukin‐1α and tumor necrosis factor α synergistically stimulate prostaglandin E 2 ‐dependent production of interleukin‐11 in rheumatoid synovial fibroblasts
Author(s) -
Mino Takemine,
Sugiyama Eiji,
Taki Hirofumi,
Kuroda Arihiko,
Yamashita Naohiro,
Maruyama Muneharu,
Kobayashi Masashi
Publication year - 1998
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/1529-0131(199811)41:11<2004::aid-art16>3.0.co;2-z
Subject(s) - protein kinase c , prostaglandin e2 , tumor necrosis factor alpha , cytokine , phorbol , interleukin , medicine , endocrinology , blot , synovial membrane , phospholipase a2 , prostaglandin e , chemistry , biology , microbiology and biotechnology , kinase , inflammation , biochemistry , enzyme , gene
Objective Interleukin‐11 (IL‐11), an IL‐6‐type cytokine, is thought to be involved in bone resorption via osteoclast differentiation. Here, we characterized the combined effect of IL‐1α and tumor necrosis factor α (TNFα), major cytokines in the rheumatoid synovium, on the production of IL‐11 by cultured rheumatoid synovial fibroblasts (RSFs). Methods The amounts of IL‐11, IL‐6, and prostaglandin E 2 (PGE 2 ) were measured by enzyme‐linked immunosorbent assay. IL‐11 messenger RNA (mRNA) levels were determined by Northern blotting. Protein expression of cytosolic phospholipase A 2 (cPLA 2 ), cyclooxygenase 2 (COX‐2), and protein kinase C (PKC) isoforms were determined by Western blotting. Results IL‐1α and TNFα synergistically stimulated RSFs to produce IL‐11 at both the mRNA and protein levels. This synergistic effect was completely inhibited by indomethacin. The inhibition was prevented by PGE 2 , indicating that the synergistic effect of IL‐1α and TNFα was PGE 2 ‐mediated. The cooperative effects of these 2 cytokines were also observed in the production of PGE 2 and the expression of 2 regulatory enzymes in PGE 2 production, cPLA 2 and COX‐2. The synergistic induction of IL‐11 by IL‐1α and TNFα was completely inhibited by a potent inhibitor of all isoforms of PKC, GF109203X. In contrast, phorbol myristate acetate, which induced a down‐regulation of PKC, degrading all PKC isoforms except atypical PKC, did not affect the induction of IL‐11. Conclusion These findings suggest that IL‐1α and TNFα synergistically stimulate the production of IL‐11 via their effects on PGE 2 production in the rheumatoid joint, and that atypical PKC may be another target for down‐regulation of IL‐11, the bone resorption‐associated cytokine.