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Twenty-six patients with systemic lupus erythematosus (SLE) showing systemic lupus activity measure (SLAM) and SLE disease activity index (SLEDAI) scores ⩽2, as well as a lower C4 concentration than the mean C4 levels of healthy controls, were selected to evaluate the C4 levels of SLE patients in remission. Serum complement (CH50), complement components (C4, C3, and B), complement split products (C4d, iC3b, and Bb), phenotypic expression of C4 allotype, C4 production by peripheral blood monocytes, peripheral blood lymphocyte subpopulation, and interferon-gamma (IFN-γ) production were examined. In patients with SLE in remission, the C4 consumption (C4d/C4) was found to increase, and this was considered to be the most important factor for determining the serum concentration of C4. However, the relevance of the C4 allotypic expression was minimal. The IFN-γ-stimulated production of C4 by peripheral blood monocytes in SLE patients in remission was also less than that of the healthy controls. The IFN-γ-stimulated production of C4 in SLE patients in remission correlated with the peripheral blood CD4-positive cells. Less IFN-γ was produced by lymphocytes of SLE in remission than by those of healthy adults. We conclude that the serum C4 levels in SLE patients in remission reflect the degree of C4 consumption as well as the disease state, rather than genetic influences such as a C4A defect. [ABSTRACT FROM AUTHOR]

In order to investigate the in vivo role of rheumatoid factor (RF), the effects of the administration of human monoclonal (m) IgM-RF and IgG-RF on the development of arthritis in mice were examined. The administration of human mRFs into mice immunized with type 11 collagen (CII) markedly enhanced the clinical score and paw swelling. The severity of arthritic joint disease with a marked infiltration of lymphoid cells, proliferation of synovial membrane, pannus formation and destruction of articular cartilage was significantly enhanced in both groups receiving RF (RF- enhanced arthritis). Skin ulcers were also observed in some or these RF-enhanced arthritis mice, whereas no such signs were observed in CII-immunized mice without mRFs. Both IgM-RF and IgG-RF increased CII-specific IgG antibodies in circulation, and these verity of arthritis correlated with the production of high titres of anti-CII antibodies. In vivo treatment of RF-enhanced arthritis mice with an anti-CD4 MoAb or an anti-CD8 MoAb inhibited the induction and progression of arthritis in these mice. Administration of RF lo severe combined immunodeficient (SCID) mice with arthritis developed by the transfer of spleen cells from CII-immunized twice, prolonged the arthritis and enhanced the severity. This murine model of RF-enhanced arthritis may provide a useful tool for analysing the pathogenesis of rheumatoid arthritis in RF-positive patients. [ABSTRACT FROM AUTHOR]

In order to investigate the possible role of IL-1 receptor antagonist (IL-lra) in patients with rheumatoid arthritis (RA), this study was undertaken to measure the amounts of IL-lra and interleukin-1β (IL-1β) protein produced by mononuclear cells (MNC) and to investigate the relationship between production of these cytokines and clinical parameters. The MNC were cultured for 24 h and the supernatants were measured for IL-lra and IL-1β by ELISA kits. MNC from peripheral blood (PB) and synovial fluid of RA patients produced significantly higher amounts of IL-lra than normal PBMNC (P < 0.01 and P < 0.05, respectively). When the IL-1β/IL-lra ratio was calculated, IL-1β/IL-lra ratios of RA PBMNC were significantly lower than those of normal PBMNC (P < 0.001). The IL-1β/IL-lra ratio of RA PBMNC was significantly higher in active RA patients than in RA patients in remission (P < 0.02). The amounts of IL-lra produced by stimulated RA PBMNC positively correlated with the joint score (P < 0.05), serum CRP levels (P < 0.05) and the amounts of IL-1β produced (P < 0.01). The amounts of IL-lra produced by unstimulated RA PBMNC did not correlate with any of the clinical parameters studied. Gold sodium thiomalate (GST), but not auranofin, increased IL-lra production . These data suggest that increased IL-lra production in RA MNC is associated with IL-1β produced, thus protecting from IL-1β-mediated immune responses, and that enhanced IL-lra production by MNC cultured with GST is one of the mechanisms by which GST shows clinical efficacy. [ABSTRACT FROM PUBLISHER]

We examined the effect of TNF-α, IL-1β and IL-6 on alkaline phosphatase (ALP) and osteocalcin (OC) production, calcification and calcium (Ca) release in human osteoblastic cell cultures obtained from human periosteum. The cells were cultured with varying concentrations of cytokines for 3 days. TNF-α and IL-1β significantly inhibited ALP production, decreased cellular Ca content, and significantly enhanced Ca release in human osteoblastic cells. IL-6, on the other hand, significantly suppressed Ca release by osteoblastic cells. These cytokines did not influence the production of OC by osteoblastic cells. The results obtained suggest that TNF-α and IL-1β may inhibit bone formation and calcification and that the effects of IL-6 on osteoblastic cells may be different from those of TNF-α or IL-1β. These effects on osteoblastic cells may be one of the mechanisms by which bone loss occurs in patients with RA. [ABSTRACT FROM PUBLISHER]

The present study was designed to establish (i) the effects of cytokines on soluble ICAM-1 (sICAM-l) production by human synovial cells (SC) and ICAM-1 expression on these cells, and (ii) the effects of sICAM-1 on lymphocyte-SC adhesion. sICAM-1 production was enhanced in parallel with ICAM-1 expression by IL-1β, TNF-α and IFN-γ, IL-4 showed no effects on ICAM-1 expression. In contrast with the transient elevation of cell-associated ICAM-1 by IL-1β, which peaked 36 h after stimulation and declined thereafter, sICAM-1 continued to accumulate in culture supernatants even after 48 h. Purified sICAM-1 was obtained from a 48h culture synovial cell supernatant by affinity chromatography using ICAM-1 monoclonal antibody. The purified sICAM-1 significantly inhibited adhesion of lymphocytes and monocytes to cytokine-stimulated synovial cells. These results suggest that sICAM-1 may modulate chronic synovitis by inhibiting ICAM-1-mediated cell-to-cell adhesion. [ABSTRACT FROM AUTHOR]

It has been suggested that IL-1 produces cartilage matrix degradation by metalloproteinases such as collagenase, and that such degradation is regulated by metalloproteinase inhibitors (TIMP). Therefore, the balance between collagenase and TIMP is an important factor for tissue destruction in inflammatory joints. In the present study the effects of cytokines on collagenase and TIMP production in chondrocytes as welt as the effects of cytokines on TIMP production in connective tissue cells were studied. IL-1β inhibited TIMP production in endothelial cells while enhancing TIMP production in synovial cells and chondrocytes. In addition, tumour necrosis factor-alpha (TNF-α) significantly inhibited and IL-6 significantly enhanced TIMP production in endothelial cells, synovial cells and chondrocytes. In the chondrocyte supernatant, collagenase activity/TIMP ratio was significantly elevated by the addition of either IL-1β or TNF-α to the cells, whereas the ratio was significantly decreased by IL-6. These results suggest that the cytokine effects on TIMP production are different among the different cell types, and that either IL-1β or TNF-α induce cartilage matrix degradation by disrupting the collagenase/TIMP balance, while, on the other hand. IL-6 protects the tissue through an opposite effect. [ABSTRACT FROM AUTHOR]

Neutrophils activated by soluble particulate stimuli generate superoxide anion and subsequently form hydrogen peroxide and other oxygen radicals. The effect of hydrogen peroxide on the complement system in normal serum was investigated. Treatment of normal serum with hydrogen peroxide resulted in a diminution of the haemolytic activity of the total and alternative complement pathways and the haemolytic titres of C3 and C5 but not of C2, in normal serum. These decreases in complement activity depended on the concentration of hydrogen peroxide added to the serum. Immunoelectrophoretic analysis of hydrogen peroxide-treated serum showed that C3 and C5 proteins were activated. Complement degradation products C3a and C5a were produced in normal serum treated with hydrogen peroxide, and 20 mM EDTA abolished C3a and C5a production in hydrogen peroxide-treated serum but 20 mM Mg-EGTA did not. Catalase completely abolished and dimethylsulphoxide and D-mannitol, hydroxyl radical scavengers, partially inhibited the hydrogen peroxide-mediated complement activation. Hypochlorite, incubated with normal serum, significantly inhibited serum haemolytic activity, and sodium thiosulphate, a reducing agent, abolished the effect of hypochlorite. Normal serum incubated with activated neutrophils showed neutrophil chemotactic activity and decreased scrum haemolytic activity, and the addition of catalase or methionine (5 mM) completely abolished the effects of activated neutrophils. These results suggest that hydrogen peroxide activates complement via an alternative pathway of complement activation and that hydroxyl radicals and other hydrogen peroxide-related species such as hypochlorite are most likely involved in hydrogen peroxide-mediated complement activation. Complement activation by oxygen radicals produced by activated neutrophils may be one of the mechanisms by which complement is activated in human immune complex diseases. [ABSTRACT FROM AUTHOR]