Abstract
The ketolide telithromycin represents a new subclass of 14-membered semisynthetic macrolides. Because there is evidence that traditional macrolides such as roxithromycin exert anti-inflammatory activity, we investigated the anti-inflammatory action of telithromycin against lipopolysaccharide (LPS)-induced acute systemic inflammation in mice in comparison with roxithromycin. CD-1 mice were injected intraperitoneally with LPS (1 mg/kg), and the effects of pretreatment with a single intraperitoneal dose of telithromycin (150 mg/kg) or roxithromycin (50 mg/kg) for 2 h on the expression and formation of tumour necrosis factor alpha (TNFalpha), interleukin-1 beta (IL-1beta), interferon gamma (IFNgamma) and inducible nitric oxide synthase (NOS-II) as well as nitric oxide (NO) were analysed at different time points after LPS-treatment. Cytokine and NOS-II mRNA abundance was examined using real-time RT-PCR. Tissue cytokine levels were determined by enzyme-linked immunosorbent assay kits (ELISA); NO levels were measured by colorimetric assay kits. Pretreatment of mice with telithromycin as well as roxithromycin similarly attenuated the LPS-induced expression and formation of TNFalpha, IL-1beta and IFNgamma. Furthermore, the LPS-induced increase of NOS-II mRNA and the formation of NO were clearly diminished. These results suggest that the ketolide telithromycin has anti-inflammatory properties like conventional macrolides due to inhibition of the production of proinflammatory cytokines, which leads to a decreased formation of NO in LPS-treated mice. Our data indicate that ketolides may have beneficial therapeutic effects independent of their antibacterial activity.
Highlights
Macrolides, such as roxithromycin, are a well-established class of antibacterial agents which are active against many Gram-positive and some Gram-negative bacteria.[1]
Because only limited information is available about ketolides with regard to their anti-inflammatory properties, we investigated the effect of a single-dose treatment of mice with telithromycin in comparison with roxithromycin on the formation of proinflammatory cytokines and nitric oxide (NO) using an in vivo model of acute LPSinduced systemic inflammation
Our present in vivo data strongly suggest that attenuation of the induction of the cytokines tumour necrosis factor alpha (TNFa), interleukin-1 beta (IL-1b) and interferon gamma (IFNg) and the subsequent induction of NO formation in response to LPS may, in part, account for clinical efficacy of ketolides in the treatment of inflammatory diseases just as well as conventional macrolides
Summary
Macrolides, such as roxithromycin, are a well-established class of antibacterial agents which are active against many Gram-positive and some Gram-negative bacteria.[1] Besides their antibacterial activity, these compounds are reported to exert anti-inflammatory and immunomodulatory activity in vitro and in vivo.[2,3,4] It has been described previously that macrolides affect several steps of the inflammatory process, such as migration of neutrophils, modulation of oxidative burst and production of cytokines.[5,6,7] In particular, it has been shown that macrolides reduce the production of proinflammatory cytokines, like tumour necrosis factor alpha (TNFa) and interleukin-1b (IL-1b), in response to lipopolysaccharide (LPS) in vitro as well as in vivo using a lowdose, long-term scheme of macrolide treatment.[3,8,9] In addition, macrolides have beneficial clinical effects in the treatment of some inflammatory airway diseases in humans, including diffuse panbronchiolitis and chronic sinusitis.[10,11,12,13] In this regard, it has been suggested that the anti-inflammatory action, but not the antimicrobial activity of macrolides, is responsible for the clinical effectiveness of these compounds in chronic inflammatory disorders
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