Azithromycin inhibits interleukin-6 but not fibrinogen production in hepatocytes infected with cytomegalovirus and chlamydia pneumoniae.
Chlamydia pneumoniae and cytomegalovirus (CMV) have been associated with the development of atherosclerosis. Inflammatory stimuli initiate the biosynthesis of fibrinogen, interleukin (IL)-6 and plasminogen activator inhibitor (PAI)-1 in the liver. Chronic infection may perpetuate the inflammatory status. We hypothesized that infection of human hepatocytes with the intracellular pathogens C pneumoniae and CMV accelerates biosynthesis of fibrinogen, IL-6, and PAI-1 but that this biosynthesis can be reduced with the use of azithromycin. HepG2 human hepatocytes were infected with C pneumoniae and CMV in vitro in the presence of 0, 0.016, 0.125, or 1 microg/mL azithromycin. We measured IL-6, PAI-1, and fibrinogen after 24, 48, 72, and 96 hours. C pneumoniae-infected hepatocytes produce IL-6 (2667 +/- 309 pg/mL vs 137 +/- 120 pg/mL in uninfected cells after 96 hours. Incubation with 0.016 microg/mL azithromycin decreased IL-6 levels to a mean of 1516 +/- 402 pg/mL, and incubation with 0.125 and 1 microg/mL azithromycin decreased IL-6 to 871 +/- 364 and 752 +/- 403 pg/mL, respectively. C pneumoniae-induced IL-6 production was time- and dose-dependent. The interaction of C pneumoniae with azithromycin treatment was significant, indicating an inhibitory effect of azithromycin on C pneumoniae-induced IL-6 production. CMV infection did not lead to IL-6 production by hepatocytes. C pneumoniae and CMV infection did not induce any changes in PAI-1 production. Fibrinogen production was increased by CMV infection after 72 hours (838 +/- 88 ng/mL; P <.01) and after 96 hours by infection with both C pneumoniae and CMV (765 +/- 100 and 846 +/- 123 ng/mL, respectively; P <.05). Azithromycin did not suppress CMV- or C pneumoniae-induced fibrinogen production. Moreover, we could not confirm an antiinflammatory effect of azithromycin in experiments with cross-titrations of azithromycin against either IL-1 or IL-6 (P >.05). Azithromycin reduces C pneumoniae-induced IL-6 production, but not fibrinogen production, by human hepatocytes. This is a result of the antimicrobial properties of azithromycin and not a direct antiinflammatory effect.
Bouwman
John J M
JJ
Laboratory and Department of Medical Microbiology, Diakonessen Hospital, Utrecht, The Netherlands. jbouwman@diakhuis.nl
Visseren
Frank L J
FL
Bouter
Paul K
PK
Diepersloot
Rob J A
RJ
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016993:Chlamydophila pneumoniae / Q000187:drug effects* / Q000502:physiology; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000096:biosynthesis*; D022781:Hepatocytes / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D000093242:Interleukin-6 Inhibitors
D000900:Anti-Bacterial Agents; D017963:Azithromycin; D005340:Fibrinogen; D015850:Interleukin-6; D017395:Plasminogen Activator Inhibitor 1; D000093242:Interleukin-6 Inhibitors