The antimalarial artemisinin synergizes with antibiotics to protect against lethal live Escherichia coli challenge by decreasing proinflammatory cytokine release.
In the present study artemisinin (ART) was found to have potent anti-inflammatory effects in animal models of sepsis induced by CpG-containing oligodeoxy-nucleotides (CpG ODN), lipopolysaccharide (LPS), heat-killed Escherichia coli 35218 or live E. coli. Furthermore, we found that ART protected mice from a lethal challenge by CpG ODN, LPS, or heat-killed E. coli in a dose-dependent manner and that the protection was related to a reduction in serum tumor necrosis factor alpha (TNF-alpha). More significantly, the administration of ART together with ampicillin or unasyn (a complex of ampicillin and sulbactam) decreased mortality from 100 to 66.7% or 33.3%, respectively, in mice subjected to a lethal live E. coli challenge. Together with the observation that ART alone does not inhibit bacterial growth, this result suggests that ART protection is achieved as a result of its anti-inflammatory activity rather than an antimicrobial effect. In RAW264.7 cells, pretreatment with ART potently inhibited TNF-alpha and interleukin-6 release induced by CpG ODN, LPS, or heat-killed E. coli in a dose- and time-dependent manner. Experiments utilizing affinity sensor technology revealed no direct binding of ART with CpG ODN or LPS. Flow cytometry further showed that ART did not alter binding of CpG ODN to cell surfaces or the internalization of CpG ODN. In addition, upregulated levels of TLR9 and TLR4 mRNA were not attenuated by ART treatment. ART treatment did, however, block the NF-kappaB activation induced by CpG ODN, LPS, or heat-killed E. coli. These findings provide compelling evidence that ART may be an important potential drug for sepsis treatment.
Wang
Jun
J
Department of Pharmacology, College of Medicine, The Third Military Medical University, Gaotanyan Street 30, Shapingba District, Chongqing 400038, People's Republic of China.
Zhou
Hong
H
Zheng
Jiang
J
Cheng
Juan
J
Liu
Wei
W
Ding
Guofu
G
Wang
Liangxi
L
Luo
Ping
P
Lu
Yongling
Y
Cao
Hongwei
H
Yu
Shuangjiang
S
Li
Bin
B
Zhang
Lezhi
L
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D000962:Antimalarials / Q000008:administration & dosage*; D037621:Artemisinins / Q000008:administration & dosage*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000276:immunology / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control*; D007249:Inflammation; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D018805:Sepsis / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control*; D012717:Sesquiterpenes / Q000008:administration & dosage*
D000900:Anti-Bacterial Agents; D000962:Antimalarials; D037621:Artemisinins; C408982:CPG-oligonucleotide; D016207:Cytokines; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D012717:Sesquiterpenes; C031327:artemisinin