Inhibition of Secretion of Interleukin-1α and Tumor Necrosis Factor Alpha by the Ketolide Antibiotic Telithromycin

Abstract

The antibiotic telithromycin was examined for its effect on secretion of interleukin-1␣ (IL-1␣), IL-1␤, IL-6, IL-10, and tumor necrosis factor alpha (TNF-␣) by lipopolysaccharide (LPS)-stimulated monocytes of eight human donors. Secretion of each cytokine was significantly increased by LPS alone, whereas treatment with telithromycin significantly inhibited secretion of IL-1␣ and TNF-␣ but not secretion of IL-1␤, IL-6, and IL-10. Telithromycin had immunomodulatory effects as a result of alteration of secretion of IL-1␣ and TNF-␣ by monocytes.Many antibiotics, when administered in vitro or in vivo in animal models, have been shown to modulate the immune response and, in particular, the inflammatory response to bacterial infections (2, 14, 18). We and others have been interested in the study of the effects of antibiotics on the production of cytokines by human monocytes (9,12,15). In an in vitro system in which lipopolysaccharide (LPS)-stimulated human monocytes are treated with various antibiotics, we observed remarkable down-regulation of production of a number of cytokines with certain macrolides (9), quinupristin-dalfopristin (10), and quinolones (11). Telithromycin is a ketolide antibiotic derived from the macrolide clarithromycin by replacement of the cladinose at C-3 with a keto group (8). This alteration results in a more stable drug and decreases the level of induction of the macrolide-lincosamide-streptogramin B resistance phenotype. We report here that telithromycin has immunomodulatory activity as a result of the down-regulation of production of proinflammatory cytokines by human monocytes.Telithromycin was obtained from Aventis Pharmaceuticals Inc. (Bridgewater, N.J.) and diluted in RPMI 1640 medium. LPS (Escherichia coli O26:B6) was purchased from Difco Laboratories, Detroit, Mich.Blood was obtained by venipuncture from healthy donor volunteers. Peripheral blood mononuclear cells were obtained and cultured as described previously (12). Briefly, cells were separated on Ficoll-Paque and Percoll (Pharmacia Biotech AB, Uppsala, Sweden) density gradients. The monocyte-enriched cell fraction was collected, washed, and resuspended in RPMI 1640 medium (with 25 mM HEPES and L-glutamine; Mediatech, Inc., Herndon, Va.) containing 10% fetal bovine serum. Characterization of monocytes was with the Naphtol AS-D chloroacetate esterase and ␣-naphthyl acetate esterase kit (Sigma Diagnostics, St. Louis, Mo.) (19). At least 90% of the cells were identified as monocytes. These were seeded into 24-well plates (Costar Corporation, Cambridge, Mass.) at a density of 10 6 cells/ml (1 ml per well) and incubated in the presence of 100 ng of LPS per ml without or with 0.5, 1, 2, 5, or 10 g of telithromycin per ml for 3, 6, or 24 h at 37°C in a 5% CO 2 incubator. Cell-free supernatants were recovered by centrifugation and stored at Ϫ20°C until assayed for interleukin-1␣ (IL-1␣), IL-1␤, IL-6, IL-10, and tumor necrosis factor alpha (TNF-␣) by enzyme-linked immunosorbent assay with commercially available reagents from PharMingen (Sa...

Macrolides Attenuate Phorbol Ester-Induced Tumor Necrosis Factor-α and Mucin Production from Human Airway Epithelial Cells

“…We found that AZM and MDM reduced PMA-induced TNF-α release from NCI-H292. These findings are in line with previous studies demonstrating the inhibitory effects of AZM, CAM and telithromycin (a derivative of CAM) on secretion of TNF-α by monocytes [21,22]. The underlying mechanism of AZM and MDM effects on mucin and TNF-α production is not clear at present.…”

Different effects of telithromycin on MUC5AC production induced by human neutrophil peptide-1 or lipopolysaccharide in NCI-H292 cells compared with azithromycin and clarithromycin

“…Although the mechanism is unclear, we speculate that this efficacy of telithromycin is due to an anti-inflammatory effect, not an antimicrobial effect. A study by Araujo et al 17 demonstrated that telithromycin inhibited the secretion of IL-1a and TNF-a by monocytes, supporting this hypothesis. However, we recently reported that telithromycin significantly reduced the number of viable bacteria, but had no effect on the proliferation of lymphocytes in an experimental murine model of chronic respiratory infection in vivo.…”

“…15 Recently, the TELICAST study showed evidence of a benefit of telithromycin to patients with acute exacerbation of asthma. 16 Although the mechanisms of this benefit remain unclear, it is possible that telithromycin also has immunomodulatory effects similar to the macrolide antibiotics both in vitro 17 and in vivo.…”

Telithromycin Inhibits the Number of Viable Bacteria but Not Lymphocyte Accumulation in a Murine Model of Chronic Respiratory Infection

“…These results suggested different mechanisms of action for CAM and TEL in chronic respiratory infection. Although previous in vitro experiments suggested that TEL has an anti-infl ammatory effect [6,7] , TEL failed to decrease the number of pulmonary lymphocytes because our investigation was performed in vivo. The mechanism of the antibacteriological effect of TEL is unclear, but it may be due to inhibition of biofi lm formation.…”

“…clarithromycin, CAM, and erythromycin) have been shown to be effective against chronic respiratory infections such as diffuse panbronchilitis [5] . However, to our knowledge, few studies have analyzed the anti-infl ammatory effects of TEL [6,7] , and the in vivo effi cacy of TEL against chronic respiratory infection has not been assessed.…”