Abstract
OBJECTIVE: The influence of a macrolide antibiotic, roxithromycin (RXM), on co-stimulatory molecule expression was examined in vitro and in vivo. MATERIALS AND METHODS: Spleen cells obtained from BALB/c mice 10 days after immunization with 8.0 microg of hemocyanin absorbed to 4.0 mg of aluminum hydroxide were cultured in the presence of 100.0 microg/ml of hemocyanin and various concentrations of RXM. We first examined the influence of RXM on cell activation by examining the proliferative response of cells and cytokine production. We also examined the influence of RXM on co-stimulatory molecule (CD40, CD80 and CD86) expressions on cultured splenic B-lymphocytes induced by in vitro antigenic stimulation using flow cytometry. In the second part of experiments, non-immunized and immunized mice were treated orally with 2.5 mg/kg of RXM once a day for 4 or 8 weeks. Splenic B lymphocytes were obtained from these mice 24 h after antigenic challenge, and co-stimulatory molecule expressions were examined by flow cytometer. RESULTS: Cell activation induced by in vitro antigenic stimulation was suppressed by RXM when cells were cultured in the presence of more than 5.0 microg/ml of the agent. Addition of RXM at a concentration of 5.0 microg/ml into cell cultures also suppressed co-stimulatory molecule (CD40, CD80 and CD86) expressions on splenic B lymphocytes, which was enhanced by antigenic stimulation in vitro. Oral RXM administration for 4 weeks clearly suppressed the enhancement of CD40 and CD86 (but not CD80) expressions on splenic B lymphocytes induced by antigenic stimulation in vivo. This suppressive activity of RXM on co-stimulatory molecule (CD40 and CD86) expressions was further strengthened by the treatment of mice for 8 weeks. Long-term treatment with oral RXM also suppressed CD80 expressions, which was not suppressed by 4-week treatment. CONCLUSION: The present results suggest that RXM exerts its immunomodulating effects through suppression of both cell activation and co-stimulatory molecule expressions induced by antigenic stimulation. These suppressive activities of RXM might contribute, in part, to the therapeutic mode of action of RXM on inflammatory diseases.
Highlights
The experiments were undertaken to examine whether the suppressive activity of RXM on antigen-induced cell activation was observed in cells stimulated by anti-CD3 monoclonal antibodies (mAbs)
Several studies have shown that long-term administration of macrolide antibiotics can favorably modify the clinical condition of inflammatory diseases.[1,2,3,4,5,6,7]
To examine the influence of RXM on the co-stimulatory pathway, it was first tested on the response of lymphocytes to in vitro antigenic stimulation by examining cell proliferation and cytokine production
Summary
Long-term administration of 14-membered macrolide antibiotics has been reported to favorably modify the clinical conditions of chronic inflammatory diseases including chronic sinusitis, diffuse panbronchiolitis, and bronchial asthma.[1,2,3,4,5] This treatment is called macrolide therapy and is used frequently in the treatment of inflammatory diseases, especially in Japan.[4,5] More recently, clinical trial therapy in England revealed that long-term administration (more than 3 months) of azithromycin, a newly synthesized macrolide antibiotic, into patients with cyctic fibrosis can improve lung functions.[6,7]Much effort has been made to understand the mechanisms underlying the efficacy of macrolide therapy, and has revealed that erythromycin, the most famous macrolide antibiotic, could inhibit chemotaxis and generation of inflammatory mediators such as O–2 and H2O2 by neutrophils when theThere is enough evidence that T cells play a central role in initiation, driving and maintenance of inflammatory responses through the secretion of several types of cytokines.[9,11] It is established that the CD28/B7 co-stimulatory pathway is essential for T-cell activation, proliferation and cytokine secretion.[12,13] A number of studies have clearly demonstrated that expressions of the co-stimulatory molecules (CD80 and CD86) on peripheral blood leukocytes from patients with inflammatory diseases were upregulated compared with normal subjects.[14,15,16] It is reported that CD80 and CD86 expressions on B cells were enhanced when the cells prepared from atopic patients and pollinosis subjects were stimulated with specific antigen in vitro.[17,18] In mouse models for inflammatory diseases, treatment of mice with anti-CD80 and antiCD86 monoclonal antibodies (mAbs) reduced several parameters of inflammatory responses such as eosinophilia and IgE hyper-production.[19,20,21] these reports suggest the importance of co-stimulatory molecules in the induction and the development of the inflammatory diseases, there is little information about the influence of RXM on costimulatory molecule expressions.[22]. The present study, was undertaken to examine whether RXM could modulate the expression of costimulatory molecules on lymphocytes in vitro and in vivo
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