In vivo efficacy of telithromycin on cytokine and nitric oxide formation in lipopolysaccharide-induced acute systemic inflammation in mice.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Lotter
Kristina
K
Department of Pharmacology und Toxicology, University of Regensburg Universitätsstr, Regensburg, Germany. kristina.lotter@chemie.uni-regensburg.de
Höcherl
Klaus
K
Bucher
Michael
M
Kees
Frieder
F
D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D048628:Ketolides / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000276:immunology; D009928:Organ Specificity; D015575:Roxithromycin / Q000627:therapeutic use; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D048628:Ketolides; D008070:Lipopolysaccharides; C440499:lipopolysaccharide, Escherichia coli O111 B4; D015575:Roxithromycin; D009569:Nitric Oxide; C106791:telithromycin