Telithromycin inhibits the production of proinflammatory mediators and the activation of NF-κB inin vitro-stimulated murine cells

Abstract

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 mitogenstimulated splenocytes. Con A-induced IFN-g 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-a (TNF-a) was suppressed by telithromycin in RAW 264.7 cultures. Lipopolysaccharide-induced activation of NF-kB transcription factor and TNF-a 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-kB 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-kB.

Anti-Inflammatory Benefits of Antibiotic-Induced Neutrophil Apoptosis: Tulathromycin Induces Caspase-3-Dependent Neutrophil Programmed Cell Death and Inhibits NF-κB Signaling and CXCL8 Transcription

“…In chicken spleen cells, active caspase-3 cleaves IB␣, producing a dominant inhibitory form of the protein and ultimately suppressing NF-B activity (4). Additionally, reports have demonstrated that some macrolides, including erythromycin, inhibit NF-B signaling and expression of proinflammatory mediators, such as CXCL8, via mechanisms that have yet to be fully elucidated (2,27,36,56). …”

“…This class of antibiotics is known to influence the recruitment and infiltration of neutrophils (23,26,31) and to alter their ability to secrete histotoxic compounds (23) and proinflammatory cytokines (31,50,53). Recent findings also indicate that some macrolides may induce cellular death by apoptosis (3,5,7,8,26) and block NF-B signaling in T lymphocytes, macrophages, or epithelial cells (27,36,56). However, the precise mechanisms underlying the anti-inflammatory and proapoptotic activities of macrolides in neutrophils remain unclear.…”

Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases

“…Proliferation and apoptosis (colourimetric assay) and cytokine production (enzyme immunoassay) of spleen cells in response to LPS and concanavalin A (Con A), and nitric oxide (NO) (colorimetric assay) and cytokine production by lipopolysaccharide-stimulated RAW 264.7 cells were determined [18]. In addition, telithromycin has been found to suppress TNF-alpha production [24].…”

The wobbly status of ketolides: where do we stand?

“…Like macrolides, ketolides also inhibit the synthesis of proinflammatory cytokines (TNF, IL-1b, IFNg) and have anti-inflammatory/immunomodulatory properties that may be beneficial to CAP patients [42][43][44][45][46].…”