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A drenomedullin (AM) is a hypotensive peptide found in human pheochromocytoma tissue, which comprises 52 amino acids with an intramolecular disulphide bond.1,2 The ring structure and amidated C-terminus of AM are critical for its receptor binding and hypotensive activity. The mature AM is synthesised as glycine extended AM followed by C-terminal amidation to assume a biologically active form in tissues. AM has a vasorelaxant effect, antagonising the vasospastic effect of endothelin-1 (ET-1). Recently, proinflammatory cytokines, such as tumour necrosis factors α (TNFα) and interleukin-1 (IL1), were found to stimulate production and secretion of AM from vascular endothelial cells and vascular smooth muscle cells in vitro, suggesting that AM interacts with the immune system.3 However, AM reduces the production of TNFα from macrophages stimulated with lipopolysaccharide. In addition, AM shows an anti-inflammatory effect that reduces the production of the IL8 family by macrophages.4 We recently reported that the concentration of AM is raised in plasma from patients with systemic sclerosis complicated by pulmonary hypertension.5
Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown cause. Inflammatory cells and cytokines such as IL1, IL6, TNFα, and IL17 are responsible, at least in part, for the pathological immune response in RA.6 Thus, we suggested that AM may play a part in the pathogenesis of RA.
Synovial fluids were obtained from nine patients with RA,7 and from six patients with osteoarthritis (OA). The concentrations of total and mature AM were measured by immunoradiometric assay. The level of ET-1 was measured by radioimmune assay. For the immunohistochemical studies, synovial tissue was obtained from the knees of three patients with RA and three with OA and stained using antihuman AM antibody and antihuman ET-1 antibody.
To explore the effect of AM on the production of IL6 from RA synoviocytes, the synovial cells obtained from three patients with RA were cultured for eight days and AM was added at various concentrations for three days. The level of IL6 in the supernatant was measured by an enzyme immunoassay.
The concentration of total AM in synovial fluid (mean (SD); pg/ml) was significantly higher in patients with RA (31.4 (14.7) pg/ml) than in patients with OA (5.5 (1.7) pg/ml (p=0.001) (web extra fig W1). The levels of mature AM were also higher in patients with RA (3.7 (2.1) fmol/l) than in patients with OA (1.1 (0.2) fmol/l) (p=0.01) (fig 1). There was no significant difference between the level of ET-1 in synovial fluids from patients with RA and OA (data not shown).
AM and ET-1 were positive around the perivascular and endothelial cells in the synovial tissue from patients with RA (fig 2, web extra fig W2). In contrast, the synovial tissue from patients with OA was negative. AM reduced constitutive production of IL6 from RA synoviocytes dose dependently. A high concentration of AM (≥10−8 mmol/l) significantly reduced constitutive production of IL6 compared with a low concentration of AM (≤10−9 mmol/l) (p=0.0029). TNFα dose dependently induced production of IL6 from RA synoviocytes (data not shown). AM did not reduce IL6 production induced by TNFα (data not shown).
Our study showed that the concentration of total and mature AM in synovial fluids was significantly higher in patients with RA than in patients with OA. In addition, by immunohistochemical staining, AM and ET-1 were shown to be positive around the perivascular area, the endothelial cells, and synoviocytes in RA synovial tissue. We have reported that osteoclasts are present in synovial tissues from patients with RA and that IL6 and soluble IL6 receptors in synovial fluids may participate in osteoclast formation.8 Thus, IL6 is responsible for joint destruction in the presence of soluble IL6 receptor through osteoclastogenesis. In this study we showed that AM reduced constitutive production of IL6 from RA synoviocytes dose dependently. Thus, our results suggest that AM in patients with RA inhibits both synovitis and osteoclastogenesis through the inhibition of IL6 production.
Adrenomedullin in synovial fluids from patients with rheumatoid arthritis inhibits interleukin 6 production from synoviocytes
Y Nanke, S Kotake, K Yonemoto, S Saito, T Tomatsu, and N Kamatani
Figure W1 Concentration of total adrenomedullin in synovial fluids from nine patients with RA and six with OA. The results are expressed as box plots. The levels of adrenomedullin were significantly higher in patients with RA than in those with OA (p=0.0015).
Figure W2 Immunohistochemical staining using anti-endothelin-1 antibody. Endothelin-1 was positive in synoviocytes in RA synovium. Original magnification �200.