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

Abstract

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.

Interactions of T Cells with Fibroblast-Like Synoviocytes: Role of the B7 Family Costimulatory Ligand B7-H3

“…1A). Expression of B7-1 or B7-2 (CD80 and CD86, respectively) by FLS was previously reported to be negligible (13,14). Similar to ICOS-L expression, B7-H1 and PD-L2 expression was negligible on FLS and did not increase with IFN-␥ stimulation (Fig.…”

“…FLS also express significant MHC class II in vivo (10), which can be reinduced in vitro (11,12). However, unlike traditional APC, FLS do not express the classic costimulatory molecules B7-1 or B7-2 (CD80, CD86) (13,14), which typically provide the second signal for full T cell activation.…”

Effect of clarithromycin on rhinovirus-16 infection in A549 cells

“…CM, for example, has been found to suppress the production of IL-1b, IL-6, IL-8, and granulocyte-macrophage colony stimulating factor [18][19][20][21], as well as to reduce ICAM-1 gene expression on nasal fibroblasts [18]. As ICAM-1 is the receptor for the major RVs, and since IL1b, IL-6, and IL-8 play significant roles in the pathophysiology of RV infection [22], CM may be able to modulate inflammatory processes during RV infection.…”

Azithromycin for cystic fibrosis

“…There is good evidence that macrolides modulate inflammatory pathways by suppressing pro-inflammatory cytokines [14]. In addition, macrolides may have more wide ranging effects on the innate immune system, modulating neutrophil function, reducing the presentation of adhesion molecules and altering expression of nitric oxide synthases [15][16][17]. Finally, macrolides may have more mechanistic effects, reducing airway mucus production and altering the biofilm phenotype of P. aeruginosa [18,19].…”