Telithromycin inhibits the production of proinflammatory mediators and the activation of NF-kappaB in in vitro-stimulated murine cells.
Telithromycin is a ketolide antibiotic with anti-inflammatory properties. To investigate the mechanisms of these effects, we examined the in vitro immunomodulatory activity of telithromycin on murine splenocytes and the murine macrophage cell line RAW 264.7. Spleen cells from BALB/c-untreated mice and RAW 264.7 macrophages were cultured in the presence of telithromycin. Proliferation and apoptosis (colorimetric assay), and cytokine production (enzyme immunoassay) of spleen cells in response to lipopolysaccharide and concanavalin A (Con A), and nitric oxide (NO) (colorimetric assay) and cytokine production by lipopolysaccharide-stimulated RAW 264.7 cells were determined. Telithromycin moderately enhanced lymphocyte proliferation in response to lipopolysaccharide and Con A, and enhanced apoptosis induced by camptothecin in mitogen-stimulated splenocytes. Con A-induced IFN-gamma production was suppressed and lipopolysaccharide-induced IL-10 production was increased in spleen cell cultures with telithromycin. Lipopolysaccharide-induced secretion of NO and tumor necrosis factor-alpha (TNF-alpha) was suppressed by telithromycin in RAW 264.7 cultures. Lipopolysaccharide-induced activation of NF-kappaB transcription factor and TNF-alpha promoter in RAW 264.7 macrophages transitorily transfected with luciferase reporter constructs was also inhibited by the ketolide. The suppressive effect of telithromycin on NF-kappaB activation was confirmed by Western blot and enzyme immunoassay. These results suggest that telithromycin exerts anti-inflammatory activity mediated by the inhibition of activation of NF-kappaB.
Department of Microbiology, Faculty of Pharmacy, University of Granada, Granada, Spain.
Magdalena
M
Leiva
Alfonso
A
Ruiz-Bravo
Encarnación
E
Moreno
Maria
M
Jiménez-Valera
D000818:Animals; D017209:Apoptosis; D002166:Camptothecin / Q000633:toxicity; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D003208:Concanavalin A / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D017930:Genes, Reporter; D007155:Immunologic Factors / Q000494:pharmacology*; D048628:Ketolides / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000276:immunology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis
D016207:Cytokines; D007155:Immunologic Factors; D048628:Ketolides; D008070:Lipopolysaccharides; D016328:NF-kappa B; D003208:Concanavalin A; D009569:Nitric Oxide; D008156:Luciferases; C106791:telithromycin; D002166:Camptothecin