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P Miossec

Publications and source records attributed to P Miossec.

At least 91 records · Page 5Linked to original sources
PubMed1995

Interleukin 4, but not interleukin 10, regulates the production of inflammation mediators by rheumatoid synoviocytes.

Rheumatoid synovitis is characterized by increased activation and proliferation of synoviocytes, which are an important source of cytokines. The role of Interleukin 4 (IL-4) and IL-10 on the production of mediators of inflammation by rheumatoid synoviocytes was studied herein. While IL-4 weakly affected the spontaneous PGE2 production, it strongly inhibited its production when cells were stimulated with IL-1 beta and TNF-alpha. IL-4 decreased by 60% to 80% the spontaneous and the IL-1 beta or TNF-alpha induced synthesis of GM-CSF. In contrast, IL-4 enhanced the spontaneous (2.6-fold), and to a lower extent (1.3-1.8-fold), the cytokine stimulated production of IL-6. This induction was not due to a passive release of pre-synthesized IL-6, since IL-4 increased the level of IL-6 mRNA expression induced by IL-1 beta. The D50 was 5 U/ml of IL-4 for both the stimulation of IL-6 synthesis and the inhibition of GM-CSF production. Kinetic studies of the action of IL-4 revealed a rapid and sustained inhibition of GM-CSF production, and a late increase of IL-6 secretion. By contrast, IL-10 had no effect on the production of either IL-6 or GM-CSF by synoviocytes. Thus, by inhibiting synoviocyte proliferation and inhibiting their secretion of PGE2 and GM-CSF, IL-4 displays on synoviocytes a series of biological effects which complements its anti-inflammatory properties on monocytes.

Arthritis, Rheumatoid↗
PubMed1995

The ability of synoviocytes to support terminal differentiation of activated B cells may explain plasma cell accumulation in rheumatoid synovium.

To understand the accumulation of plasma cells within RA synovium, the ability of rheumatoid synoviocytes to support the differentiation of B cells into plasma cells was explored. Tonsillar B lymphocytes cultured over confluent monolayers of synoviocytes, secreted threefold more Igs (mainly IgM) than B cells cultured directly on plastic well. More importantly, synoviocytes enhanced by 14-fold the production of Igs (mainly IgG) by B cells costimulated with Staphylococcus aureus Cowan (SAC) particles. IL-10 and, in a lower extent, IL-2 increased Ig secretion in cocultures, and their combination was synergistic. In the presence of SAC, IL-2, and IL-10, synoviocytes increased by 13-884-fold the production of IgG, which reached 0.19 ng/cell per day. RA as well as normal synoviocytes were more potent than other adherent cell lines to support terminal B cell differentiation. Synoviocyte activity involved both a support of B cell survival, and an induction of the terminal differentiation of B cells into mature plasma cells with typical morphology, high levels of intracytoplasmic Igs, and CD20- CD38high surface expression. The present observation should permit the identification of molecules involved in the maturation of B cells into plasma cells, and in their accumulation in rheumatoid synovium.

Antibodies, Monoclonal↗
PubMed1994

The vitronectin receptor (alpha v beta 3) is implicated, in cooperation with P-selectin and platelet-activating factor, in the adhesion of monocytes to activated endothelial cells.

In this study we have investigated the presence on endothelial cells of potential glycoprotein receptors, other than P-selectin, which are involved in the adhesion of monocytes at the early stages of activation. We report that the majority of cells binding to thrombin-activated endothelial cells from a peripheral blood mononuclear cell (PBMC) preparation are monocytes. The adhesion of PBMC to thrombin-activated, but not resting, endothelial cells was inhibited (66%) by a monoclonal antibody (mAb) directed against alpha v beta 3. Elutriated monocytes or a monocytic cell line (U937) were also inhibited by this antibody, its F(ab)'2 fragments and three other anti-(alpha v beta 3) mAbs. alpha v beta 3 isolated from endothelial-cell lysates significantly inhibited the adhesion of monocytes and U937 cells to endothelial cells. A peptide motif (RGDF) known to interact with alpha v beta 3 inhibited U937 cell adhesion to activated endothelial cells by 53%. Finally, an anti-(P-selectin) mAb (LYP20) or a platelet-activating factor (PAF)-receptor antagonist (WEB 2086) inhibited monocyte adhesion to activated endothelial cells. This study shows for the first time that alpha v beta 3 is implicated, in addition to P-selectin and PAF, in the adhesion of monocytes to activated endothelial cells.

Amino Acid Sequence↗
PubMed1994

Interleukin-4 inhibits bone resorption through an effect on osteoclasts and proinflammatory cytokines in an ex vivo model of bone resorption in rheumatoid arthritis.

OBJECTIVE: To assess local bone resorption in the context of rheumatoid synovitis and its modulation by interleukin-4 (IL-4). METHODS: We developed an ex vivo model of bone resorption using juxtaarticular samples of bone obtained during joint surgery. We studied the histomorphometric parameters of bone resorption and the regulation of the production of IL-6, leukemia inhibitory factor (LIF), and the collagen cross-link pyridinoline, which is released during bone resorption in vivo. RESULTS: This was a sensitive and dynamic model of bone resorption. The bone samples produced high levels of pyridinoline and as much cytokine as synovium pieces obtained from the same joint. IL-4 induced a 70% reduction of IL-6 and LIF production by bone pieces and reduced pyridinoline levels. Histomorphometric studies performed on bone samples indicated a 35% increase in the mean total bone area after 7 days of treatment with IL-4. More importantly, with IL-4, osteoclasts were not detectable in the bone sections. CONCLUSION: The inhibitory effect of IL-4 on bone resorption extends our knowledge of its antiinflammatory properties and suggests that the inflammatory cytokine imbalance in rheumatoid synovium also contributes to defects in bone resorption in RA.

Adult↗
PubMed1994

Different cytokine production profiles of gamma delta T cell clones: relation to inflammatory arthritis.

This study was performed to investigate whether gamma delta T cells could also be divided into subsets, identified by a cytokine profile, as described for alpha beta T helper (Th) cell subsets. Cytokine production was studied in 22 gamma delta T cell clones obtained from the synovial fluid and peripheral blood of one patient with inflammatory arthritis and compared to that of 26 alpha beta T cell clones of the same and different patients. Interferon-gamma (IFN-gamma) was produced by 18 (82%) and interleukin-4 (IL-4) by 17 (77%) out of 22 gamma delta T cell clones, respectively. In contrast, IL-10 was not produced, except at very low level in one case. The mean levels of IL-4 were lower for clones derived from synovial fluid. When considering the production of IFN-gamma as an indicator of Th1 and that of IL-4 as an indicator of Th2, respectively, the most common pattern was a gamma delta Th1-like pattern, with the combination of high levels of IFN-gamma and low levels of IL-4. This pattern was found in V delta 1+ clones, all from synovial fluid. Additional patterns were also observed: a mixed, probably gamma delta Th0-like pattern with a more balanced production of both IFN-gamma and IL-4; a gamma delta Th1 pattern with the production of IFN-gamma alone; a gamma delta Th2 pattern with the production of IL-4 alone. These three patterns were also seen in blood gamma delta T cells which were all V delta 2, indicating that these patterns were independent of the V delta phenotype. gamma delta T cell clones produced lower levels of IFN-gamma (p = 0.001) and higher levels of IL-4 than alpha beta clones (p < 0.02). These differences in cytokine production between alpha beta and gamma delta subsets and within these subsets may contribute to their respective role in chronic inflammation.

Adolescent↗
PubMed1994

Interleukin-4 but not interleukin-10 inhibits the production of leukemia inhibitory factor by rheumatoid synovium and synoviocytes.

The expression of the proinflammatory cytokine leukemia inhibitory factor (LIF) has been reported in the cartilage and synovium of rheumatoid arthritis (RA) patients. Here, we show that high levels of LIF were constitutively produced by cultures of synovium pieces. Low levels of LIF were produced spontaneously by isolated synoviocytes, but interleukin (IL)-1 beta caused a fourfold enhancement of this secretion. The anti-inflammatory cytokine IL-4 reduced the production of LIF by synovium pieces by 75%, as observed earlier with IL-6, IL-1 beta and tumor necrosis factor (TNF)-alpha. IL-4 had a direct effect since it inhibited LIF production by unstimulated and IL-1 beta- or TNF-alpha-stimulated synoviocytes. Conversely, IL-4 enhanced the production of IL-6, which shares with LIF biological activities and receptor components. The inhibitory effect of IL-4 was dose dependent and was reversed using a blocking anti-IL-4 receptor antibody. Similar inhibitory action of IL-4 on LIF production was observed on synovium pieces from patients with osteoarthritis and on normal synoviocytes. IL-10, another anti-inflammatory cytokine acting on monocytes, had no effect on LIF production by either synovium pieces or isolated synoviocytes. Thus, the production of LIF by synovium tissue was inhibited by IL-4 through both a direct effect on synoviocytes and an indirect effect by inhibition of the production of LIF-inducing cytokines.

Arthritis, Rheumatoid↗
PubMed1994

Human interleukin 4.

Human IL-4 is a mature glycoprotein of 129 amino acids, mostly secreted by activated T cells. It is a pleiotropic cytokine which acts on T and B lymphocytes, monocytes, polymorphonuclears, fibroblasts and endothelial cells. In addition, it acts at various stages of cell differentiation, and its effects are also dependent on the cytokine environment. In particular, IL-4 blocks some of the effects of IL-2 whereas interferon-gamma blocks some of the effects of IL-4. In vitro and in vivo experiments in mouse and in vitro experiments in man have shown that IL-4 plays a crucial role in the induction of IgE production whereas interferons counteract this effect. Human IL-4 binds to a high-affinity receptor which is composed at least of one 130 kDa glycoprotein of 800 amino acids which is a member of the newly described hematopoietin receptor superfamily. IL-4 may prove useful as an anti-tumoral and anti-inflammatory agent.

B-Lymphocytes↗
PubMed1993

IL-4 inhibits growth factor-stimulated rheumatoid synoviocyte proliferation by blocking the early phases of the cell cycle.

A major feature of rheumatoid arthritis is an uncontrolled proliferation of synoviocytes. This is consistent with the active production of factors such as platelet-derived growth factor (PDGF) and IL-1 by the synovitis, which act in vivo as well as in vitro as potent synoviocyte growth factors. We have previously shown that IL-4 is able to inhibit growth factor production in an ex vivo model of synovitis. Herein, we show that IL-4 strongly inhibited PDGF and IL-1 beta stimulated rheumatoid arthritis synoviocyte proliferation in a dose-dependent manner and through its 130 kDa receptor. This antiproliferative effect of IL-4 directly correlated with a blockade of the synoviocyte cell cycle at the G0 + G1 phases. We also observed that IL-4 induced striking morphologic changes in IL-1 beta or PDGF-stimulated synoviocytes, including increased volume and granulosity. These changes led to major perturbations of the cell monolayer, associated with a marked decrease of synoviocyte viability. Taken together, these data indicate that IL-4 inhibits growth factor-induced proliferation of synoviocytes by interfering with the cell cycle, and by decreasing cell survival.

Arthritis, Rheumatoid↗
PubMed1993

Interferon gamma inhibits interleukin 10 production by monocytes.

Interleukin 10 (IL-10) was first described for its ability to inhibit interferon gamma (IFN-gamma) production. Herein, we studied the balance between IFN-gamma and IL-10 production by human peripheral blood mononuclear cells (PBMC) in response to Staphylococcus aureus Cowan (SAC) or lipopolysaccharide (LPS). Monocyte depletion reduced IL-10 production by 90% and resulted in an increased IFN-gamma production. Addition of anti-IL-10 antibody to PBMC cultures also strongly increased IFN-gamma production. In contrast, among various cytokines, only IFN-gamma strongly reduced IL-10 synthesis by SAC- or LPS-activated PBMC and monocytes. Thus, IFN-gamma has proinflammatory effects through the combination of two mechanisms: (a) induction of early tumor necrosis factor alpha (TNF-alpha) and IL-1 beta synthesis; and (b) inhibition of the delayed production of IL-10, an inhibitor of TNF-alpha and IL-1 beta synthesis. Taken together, the present data indicate that IFN-gamma and IL-10 antagonize each other's production and function.

Cells, Cultured↗
PubMed1993

Increased production of soluble CD23 in rheumatoid arthritis, and its regulation by interleukin-4.

OBJECTIVE: To assess CD23 status in rheumatoid arthritis (RA) patients, as defined by the levels of CD23 expression on peripheral blood mononuclear cells (PBMC), the levels of soluble CD23 (sCD23) in sera, and the production of sCD23 by PBMC cultures and its regulation by interleukin-4 (IL-4). METHODS: CD23 expression as determined by double fluorescence-activated cell sorter analysis and sCD23 production as determined by immunoradiometric assay were investigated in 24 RA patients and 21 controls. Soluble CD23 was measured in sera and supernatants of PBMC, activated with polyclonal activators (pokeweed mitogen [PWM] or Staphylococcus aureus Cowan strain 1, [SAC]) used either alone or in combination with IL-2 or IL-4. RESULTS: The percentage of B cells expressing CD23 and serum levels of sCD23 were increased in patients with RA. IL-4 was a potent inducer of sCD23 production in supernatants, whereas IL-2 was inactive. Costimulation with SAC or PWM did not increase the effect obtained with IL-4 alone. When sCD23 levels in RA and control supernatants were compared, spontaneous production was found to be increased in RA PBMC: This difference from control values was even more pronounced when sCD23 levels in PBMC and purified B cells in response to IL-4, either alone or in combination with SAC or PWM, were tested. In the same supernatants, the increased secretion of sCD23 induced by IL-4 was associated with an inhibitory effect of IL-4 on Ig production, a phenomenon that was more pronounced in RA PBMC than in controls. CONCLUSION: CD23 status in RA is characterized by increased expression of CD23 on B cells, increased production of sCD23 in sera and supernatants, and increased sensitivity of RA PBMC and B cells to IL-4.

Adolescent↗
PubMed1993

Rheumatoid inflammatory T-cell clones express mostly Th1 but also Th2 and mixed (Th0-like) cytokine patterns.

This study was performed in order to characterize whether T cells from rheumatoid synovial inflammation belong to the Th1- or Th2-like functional subsets. Cytokine production was studied in 26 CD4+ alpha beta+ and 2 CD8+ alpha beta T-cell clones from the synovial fluid, the synovial membrane and peripheral blood of 5 patients. Fifteen of the CD4+ clones were raised against various mycobacterial antigens and 11 CD4+ clones and 2 CD8+ clones were raised unspecifically using PHA and/or IL-2. The specificities of these clones are not known. In the mycobacterial antigen-specific group, all CD4+ alpha beta T-cell clones produced IFN-gamma at high levels, while the production of IL-4 was generally absent or low (< 1 ng/ml), consistent with a Th1-like profile. Some of these clones, however, also produced various amounts of IL-10 which has been regarded as a Th2 product but can be produced also in lower amounts by Th1 cells. One HSP-65-specific clone produced levels of IL-4 and IL-10 in the same order as that of IFN-gamma, thus appearing to be Th0-like. Among the 11 unspecific CD4+ clones, 7 showed a Th1-like pattern but with lower levels of IFN-gamma than the antigen-specific clones. However, three clones did not produce any IFN-gamma activity but produced IL-4 and one of them also produced distinct amounts of IL-10, compatible with a Th2-like pattern. In addition, one of the clones also showed an almost equally strong IFN-gamma and IL-4 production, thus most likely representing a Th0-like clone.

Adolescent↗
PubMed1993

Cytokine and anti-cytokine strategies in inflammatory reaction modulation.

Evidence of the importance of a cytokine cascade in the induction and control of the inflammatory reaction is increasing. Although cytokines are required in the inflammatory process in response to infection or injury, their overproduction, particularly that of interleukin-1 (IL-1) and tumor necrosis factor (TNF), can lead to local/systemic pathology. Selective inhibition of the synthesis or of the action of specific cytokines may be of therapeutic benefit. Various strategies for blocking IL-1 and TNF activities have been presented. While selective inhibition of cytokine synthesis is still in the early experimental phase, specific blockade of soluble cytokine action following synthesis and release from cells is undergoing preliminary clinical trials in humans. Animal data suggest that antimonoclonal therapy such as monoclonal antibodies to TNF, IL-1 receptor antagonists or soluble receptors to TNF and IL-1 can be effective in the modulation of the inflammatory reaction. Modulation of the cytokine network in some diseases might also include the use of anti-inflammatory cytokines. Nonetheless, the possibilities of side effects due to impaired host-defense mechanisms with the IL-1 or TNF blockade must also be taken into consideration.

Animals↗