We investigated whether a 6-h endurance run changes cytokine plasma concentrations and lipopolysaccharides (LPS) stimulated ex vivo production of cytokines in a whole blood culture of 19 well-trained athletes. The average distance covered was 65.1 +/- 8.64 (SD) km. At the end of the exercise, the mean plasma concentration of interleukin-1-receptor agonist (IL-1ra), which was 188 pg/ml 24 h before finish, increased to 886 pg/ml (P < 0.0005). The mean plasma interleukin-6 concentration increased from 18.5 +/- 4.2 to 71.5 +/- 33.3 pg/ml (P < 0.0001). The increase of neutrophils correlated with the increase of IL-1ra concentrations (r = 0.58, P < 0.005). We could not detect an effect of exercise on plasma concentrations of interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha). The ex vivo LPS-stimulated production of IL-1 beta in athletes 24 h before the run was significantly higher than in sedentary controls. Exercise induced a decrease of LPS-stimulated production of IL-1 beta and TNF-alpha, whereas production of IL-1ra was unchanged. These results show that prolonged exercise elicits a selective downregulation of the proinflammatory cytokine production and upregulation of the cytokines IL-1ra and interleukin-6.

Objective. To evaluate Fc␥ receptor (Fc␥R) expression on synovial macrophages from rheumatoid arthritis (RA) patients and to determine whether this expression correlates with the production of the proinflammatory cytokines tumor necrosis factor ␣ (TNF␣), interleukin-1␤ (IL-1␤), IL-12, and matrix metalloproteinase 1 (MMP-1). We also sought to determine whether mature macrophages from RA patients express aberrant levels of Fc␥RI, Fc␥RII, and Fc␥RIII, and to determine the production of inflammatory mediators after immune complex (IC) stimulation.Methods. Immunohistochemistry was performed on cryostat sections of synovial biopsy specimens obtained from 27 RA patients and 5 controls. Fc␥R I, II, and III were detected, as well as the proinflammatory mediators IL-1, TNF␣, IL-12, and MMP-1. Monocytes were isolated from the blood of 10 RA patients and 10 healthy controls and cultured for 7 days with macrophage colony-stimulating factor to obtain macrophages. Using fluorescence-activated cell sorting, the expression of Fc␥RI, Fc␥RII, and Fc␥RIII was determined. On day 7, macrophages were stimulated with heat-aggregated gamma globulins (HAGGs) for 24 hours. Production of cytokines was measured using enzyme-linked immunosorbent assay, and production of gelatinases/ collagenases was measured by degradation of fluorescent gelatin.Results. Immunohistochemistry showed higher Fc␥RII and Fc␥RIII expression in RA synovium than in controls. Fc␥RII and Fc␥RIII, but not Fc␥RI, were highly correlated with the number of synovial macrophages. Consistent with this, TNF␣ expression correlated positively with Fc␥RIII expression. Moreover, MMP-1 expression strongly correlated with Fc␥R I, II, and III expression. Mature macrophages from RA patients showed significantly enhanced expression of Fc␥RII and Fc␥RIII compared with controls. Twentyfour hours after stimulation of RA macrophages with HAGGs, significantly higher production of TNF␣ and gelatinase/collagenase was measured.Conclusion. RA synovium and mature RA macrophages express significantly elevated levels of Fc␥RII and Fc␥RIII, resulting in much higher production of TNF␣ and gelatinase/collagenase after IC stimulation. These data suggest that disturbed expression of Fc␥R on mature synovial macrophages is involved in the pathology of RA.

No abstract

Background: Dendritic cells orchestrate pivotal immunological processes mediated by the production of cytokines and chemokines. Objective: To assess whether neutralisation of tumour necrosis factor a (TNFa) during maturation of dendritic cells affects their phenotype and behaviour, which might explain the beneficial effects of TNFa neutralisation in rheumatoid arthritis. Methods: Immature and fully matured dendritic cells were cultured from blood monocytes from patients with rheumatoid arthritis and healthy controls following standardised protocols. TNFa was neutralised by addition of the p55 soluble TNFa receptor, PEGsTNFRI. The effect of TNFa neutralisation on the phenotype (CD14, CD16, CD32, CD64, CD80, CD83, CD86, and MHC) of dendritic cells was investigated by flow cytometry. Expression of chemokines (CCL17, CCL18, CCL19, CCL22, CCL3, and CXCL8) and production of IL1b and IL6 during dendritic cell differentiation and maturation were examined. Results: Neutralisation of TNFa during the differentiation and maturation of dendritic cells did not result in an altered dendritic cell phenotype in the rheumatoid patients or the healthy controls. In contrast, the expression of CCL17, CCL18, CCL19, CCL22, CCL3, and CXCL8 by dendritic cells was significantly reduced when TNFa activity was inhibited during lipopolysaccharide triggered dendritic cell maturation. The production of IL1b and IL6 by mature dendritic cells was inhibited by PEGsTNFRI. Conclusions: Inhibition of TNFa activity during dendritic cell maturation leads to the development of semimature cells. These data suggest a novel pathway by which the neutralisation of TNFa might exert its therapeutic effects.

No abstract