Clarithromycin and azithromycin induce apoptosis of activated lymphocytes via down-regulation of Bcl-xL

Mizunoe, Syunji; Kadota, Jun‐ichi; Tokimatsu, Issei; Kishi, Kenji; Nagai, Hirokazu; Nasu, Masaru

doi:10.1016/j.intimp.2004.05.011

Cited by 59 publications

(42 citation statements)

References 30 publications

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“…21,22 Azithromycin along with clarithromycin are reported to induce apoptosis of activated lymphocytes. 23 In previous studies in our laboratory, azithromycin was also observed to cause reversible autophagy in rabbit tracheal SMCs, but not apoptosis, as well as reversible inhibition of the proliferation. 9 Interestingly, azithromycin seems to affect cell proliferation by inducing both autophagy and apoptosis, with the threshold between the two procedures being affected by cell type.…”

Section: Discussionmentioning

confidence: 76%

Azithromycin reduces the viability of human bronchial smooth muscle cells

et al. 2010

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The macrolide antibiotic azithromycin has an antiproliferative and autophagic effect on rabbit tracheal smooth muscle cells (SMCs). The purpose of this study is to investigate the effect of azithromycin on human bronchial SMCs. Human bronchial SMCs were treated with azithromycin (10 À5 M) in the presence or absence of 10% fetal bovine serum (FBS). Cell number was estimated using the Cell Titer 96 AQ ueous One Solution Assay. Induction of autophagy was studied by observation of cell morphology in cells treated or not with the autophagy inhibitor, 3-methyladenine (3-MA), as well as by Lysotracker Red staining of lysosomes. Activation of apoptosis was assessed with flow cytometry after annexin staining. Incubation with azithromycin for 24, 48 or 72 h reduced viability in FBS-deprived cells, as well as cells cultured in FBS-containing medium. Azithromycin treatment resulted in the formation of cytoplasmic vacuoles that could not be prevented by 3-MA. Furthermore, 3-MA did not reverse the effect of azithromycin on the viability of SMCs. There was an increase in the number of lysosomes in cells treated with azithromycin. Finally, azithromycin increased the percentage of early apoptotic cells. In conclusion, azithromycin reduces the viability of human bronchial SMCs possibly by leading to apoptotic cell death.

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Section: Discussionmentioning

confidence: 76%

Azithromycin reduces the viability of human bronchial smooth muscle cells

et al. 2010

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“…As has been shown previously, erythromycin inhibits hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium [11], roxithromycin inhibits proliferation of human coronary artery SMCs [12], and rapamycin and its analogue SAR943 inhibit proliferation of human epithelial and SMCs [13], while clarithromycin and azithromycin induce apoptosis of activated lymphocytes [14]. In order to investigate whether azithromycin exerts a similar effect on airways, we studied the effect of azithromycin on airway SMC proliferation and the pathways involved.…”

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confidence: 91%

Azithromycin has an antiproliferative and autophagic effect on airway smooth muscle cells

et al. 2009

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Azithromycin is used in long-term, low-dose treatment of airway diseases where airway wall remodelling is present. Since it improves total score symptom and respiratory function of such patients, we hypothesise that azithromycin's additional clinical benefits are due to an inhibition of airway smooth muscle cell (SMC) proliferation.Rabbit tracheal SMCs were treated with azithromycin (10 -5 to 10 -6 M) in the presence or absence of 10% fetal bovine serum (FBS). The proliferation was estimated using the Cell Titer 961 AQ ueous One Solution Assay (Promega, Madison, WI, USA). Cell viability was assessed with Trypan blue staining and flow cytometry after 7-aminoactinomycin D (7-AAD) staining. Induction of autophagy was studied by indirect immmunofluorescence and/or Western blotting with antibodies against human smooth muscle a-actin, beclin 1, light chain 3 and caspase 3. The involvement of the phosphoinositide 3-kinase pathway was investigated with the inhibitors LY294002 and wortmannin. Incubation with azithromycin for 72 h in the presence of FBS reduced SMC proliferation and viability in a dose-dependent manner. Azithromycin treatment was accompanied by the formation of cytoplasmic vacuoles, characteristic of autophagy. All these effects were reversible after azithromycin removal and prevented by the autophagy inhibitor, 3-methyladenine, or LY294002, but not by wortmannin.In conclusion, azithromycin reduces proliferation and causes autophagy of airway SMCs.KEYWORDS: Airway smooth muscle cells, autophagy, azithromycin, proliferation M acrolide antibiotics are widely used for the treatment of airway diseases. Lowdose, long-term macrolide therapy has been reported to be very effective in patients with chronic airway diseases, such as diffuse panbronchiolitis, chronic bronchitis and bronchial asthma [1][2][3][4][5]. In many of these diseases, airway wall remodelling is present. Airway wall remodelling includes thickening of the reticular membrane, proliferation of the smooth muscle cells (SMCs) and increase in both number and size of vessels [6,7].The improvement of pulmonary function, total score symptom and quality of life with macrolides is mainly attributed to their antimicrobial and anti-inflammatory activity. However, data available from studies on airway smooth muscle show an effect of macrolides on the contractility of airway smooth muscle. Specifically, erythromycin inhibits cholinergic neuroeffector transmission in the airways [8,9] and azithromycin has a direct relaxant effect on precontracted rabbit airway smooth muscle [10].It is possible that azithromycin has an additional effect in airway SMC proliferation. As has been shown previously, erythromycin inhibits hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium [11], roxithromycin inhibits proliferation of human coronary artery SMCs [12], and rapamycin and its analogue SAR943 inhibit proliferation of human epithelial and SMCs [13], while clarithromycin and azithromycin induce apoptosis of activated lymphocytes [14]. In o...

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“…[2] They speculated that macrolide induced the apoptosis of lymphocytes via downregulation of bcl-xL, an anti-apoptotic protein. [12] We have also previously reported a case of follicular B-cell and diffuse large B-cell lymphomas successfully treated using CAM. [3,4] CAM is known to induce the downregulation of bcl-2, an anti-apoptotic protein, [13] and lymphoma cells from our previous cases were positive for bcl-2, so we speculated that CAM induced the apoptosis of lymphoma cells.…”

Section: Tcpmentioning

confidence: 88%