Effects of lobenzarit disodium on human endothelial cells. Lobenzarit disodium inhibits proliferative response, HLA–DR antigen expression, and T cell adherence toward endothelial cells

Kawakami, Atsushi; Eguchi, Katsumi; Ueki, Yukitaka; Migita, Kiyoshi; Ida, Hiroaki; Nakao, Hideto; Kurata, Akihiko; Fukuda, Takaaki; Nagataki, Shigenobu; Ishimaru, Tadayuki; Kurouji, Ken-Ichi; Fujita, Nagatoshi

doi:10.1002/art.1780340307

Cited by 13 publications

(3 citation statements)

References 29 publications

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“…The mechanism of action of disease-modifying anti-rheumatic drugs (DMARDs) can be summarized as follows: (i) inhibition of cytokine activity/production [16][17][18]; (ii) inhibition of adhesion/costimulatory molecule expression [19][20][21]; (iii) alteration of mononuclear cell population [20,21]; (iv) inhibition of cell growth [22][23][24][25]. Our results demonstrated that clarithromycin produced most of these effects on synoviocytes.…”

Section: Discussionmentioning

confidence: 94%

Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells

Matsuoka

Eguchi

Kawakami

et al. 1996

Clinical and Experimental Immunology

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SUMMARYThis study was undertaken to investigate the immunomodulatory effect of clarithromycin against synovial fibroblast-like cells (synoviocytes). Synovial tissue obtained from rheumatoid arthritis (RA) or osteoarthritis (OA) patients was enzymatically digested to separate synoviocytes. The synoviocytes were cultured with or without cytokines in the presence of various concentrations of clarithromycin. The expression of costimulatory molecules was examined on the surface of the synoviocytes, using specific MoAbs and flow cytometry. The production of cytokines by synoviocytes was also measured using an immunoenzymatic assay. Finally, autologous T cells were stimulated by interferon-gamma (IFN-)-treated synoviocytes in response to purified protein derivative (PPD). In some experiments, MoAbs specific for costimulatory molecules or clarithromycin were added and 3 H-thymidine incorporation was counted. Intercellular adhesion molecule-1 (ICAM-1), LFA-3 and vascular cell adhesion molecule-1 (VCAM-1) were detected on the surface of both RA and OA synoviocytes. However, ICAM-2, B7-1 and B7-2 were not detected, and cytokines failed to induce these molecules. Both spontaneous and upregulated expression of ICAM-1, LFA-3 and VCAM-1 by IFN-, IL-1 or 12-o-tetradecanoyl phorbol 13-acetate (TPA) were markedly suppressed by clarithromycin in a dose-dependent manner at concentrations between 0 . 1 and 10 g/ml. The production of IL-1, IL-6, IL-8, granulocyte colonystimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) but not IL-1 and tumour necrosis factor-alpha (TNF-) by synoviocytes was detected. Clarithromycin significantly suppressed the production of these cytokines, but did not enhance IL-10 production. Finally, autologous T cells were stimulated by IFN--treated synoviocytes in response to PPD. As clarithromycin suppressed HLA-DR and costimulatory molecule expression was enhanced by IFN-, autologous T cell proliferation was markedly inhibited by clarithromycin. Clarithromycin has a considerable immunosuppressive effect on synoviocytes by inhibiting costimulatory molecule expression, cytokine production and antigen-specific T cell proliferation induced by synoviocytes.

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Section: Discussionmentioning

confidence: 94%

Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells

Matsuoka

Eguchi

Kawakami

et al. 1996

Clinical and Experimental Immunology

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“…If the implications of our in vitro findings are correct, then either CCA is a pro-drug or its effects are indirectly due to other important effects on the immune system [44].…”

Section: The Effects On Inflammatory Mediator Productionmentioning

confidence: 89%

Complete prevention of the clinical expression of adjuvant-induced arthritis in rats by cyclosporin-A and lobenzarit: The regulation of lymph node cell populations and cytokine production

et al. 1996

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A single dose of either cyclosporin-A (CsA) or lobenzarit (CCA) given with an arthrogenic adjuvant completely prevented expression of experimental adjuvant arthritis in rats. The aim of this study was to understand how these drugs prevented the arthritis expression by studying the popliteal lymph nodes draining the arthritic joints at various times after adjuvant injection. Neither drug affected the proliferation in popliteal lymph nodes at the time arthritis was normally expressed, however, there was a marked change in the types of cells present. Immunofluorescence assays showed a reduction in the proportion of CD4+ cells, while the proportion of B-lymphocytes was almost doubled. This coincided with a marked elevation in the ability of these cells to produce interleukin (IL)-6. At the same time production of other cytokines (IL-2, tumour necrosis factor (TNF) and interferon (IFN)-gamma) was not greatly affected. However, one day after adjuvant injection IL-2 and IFN-gamma production was reduced. In vitro experiments showed that IL-6 production by lymphoid cells was relatively unaffected by CsA and CCA but IL-2, TNF and IFN-gamma were suppressed by CsA. The results indicate that CsA and CCA may modify the response to the arthritic adjuvant by specifically inhibiting IL-2, TNF and IFN-gamma production at the time of adjuvant injection. The lack of inhibition of IL-6 by these drugs reveals it may not play a key role in the initiation of this model of chronic inflammation.

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“…The results from three separate experiments are expressed as the mean ±s.d. * /*< O' Ol rer.iii.\-T cell adhesion to synovial cells with incubalion time 0 h. described elsewhere [10], Briefly, endothelial cells (2 x lO^/well) were cultured for 24 h in triplicate in fibroncctin-coalcd 96-weII flat-bottomed microlitre plates (tostar. Cambridge, MA) in 200 /i\ of culture medium in the presence of varying concentrations of reagents.…”

Section: Endothelial Cell or Synovial Celt Monotayer Adhesion As\aymentioning

confidence: 99%

Interferon-alpha and dexamethasone inhibit adhesion of T cells to endothelial cells and synovial cells

Eguchi

Kawakami

Nakashima

et al. 1992

Clinical and Experimental Immunology

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We investigated whether interferon-gamma (IFN-gamma), interferon-alpha (IFN-alpha) and glucocorticoids affected the adhesion of T cells to human umbilical endothelial cells or human synovial cells. About 30% of peripheral blood T cells could bind to unstimulated endothelial cells, but only a few T cells could bind to unstimulated synovial cells. When both endothelial cells and synovial cells were cultured with recombinant IFN-gamma (rIFN-gamma), the percentage of T cell binding to both types of cells increased in a dose-dependent manner. rIFN-alpha and dexamethasone blocked the T cell binding to unstimulated endothelial cells. Furthermore, rIFN-alpha and dexamethasone suppressed T cell binding to both endothelial cells and synovial cells stimulated by IFN-gamma, and also inhibited intercellular adhesion molecule-1 (ICAM-1) expression on both endothelial cells and synovial cells stimulated by IFN-gamma. These results suggest that IFN-alpha and glucocorticoids may inhibit T cell binding to endothelial cells or synovial cells by modulating adhesion molecule expression on these cells.

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Effects of lobenzarit disodium on human endothelial cells. Lobenzarit disodium inhibits proliferative response, HLA–DR antigen expression, and T cell adherence toward endothelial cells

Cited by 13 publications

References 29 publications

Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells

Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells

Complete prevention of the clinical expression of adjuvant-induced arthritis in rats by cyclosporin-A and lobenzarit: The regulation of lymph node cell populations and cytokine production

Interferon-alpha and dexamethasone inhibit adhesion of T cells to endothelial cells and synovial cells

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