Pretreatment with interleukin-6 small interfering RNA can improve the survival rate of polymicrobial cecal ligation and puncture mice by down regulating interleukin-6 production.
Interleukin-6 (IL-6) is considered to be an early marker of severe sepsis that is associated with increased morbidity and mortality. Therefore, we pretreated male ICR mice with IL-6 small interfering RNA (siRNA) before cecal ligation and puncture (CLP) and observed the changes in their survival in response to down regulation of IL-6, as well as the role of Th subsets during sepsis. In addition, sham and CLP operated mice were sacrificed at different time points to determine the serum IL-6 levels during early and late sepsis. IL-6 siRNA pretreated septic mice showed markedly extended survival (23.3%) up to 10 days and significantly reduced serum IL-6 levels at day 5 (209.90 ± 0.50 pg/ml; P<0.0001) when compared to CLP mice at day 1. Furthermore, IL-6 mRNA and protein were highly expressed during early sepsis in CLP mice at day 1 and mRNA was not detected in IL-6 siRNA treated CLP mice at days 1 or 5 and serum level of IL-6 was also decreased significantly (P<0.01). In addition, the mRNA expression of C5aR, ROR-γt, PU.1 and protein expression of IL-17 were high at day 5 in IL-6 siRNA treated mice. Taken together, the results of the present study demonstrate that pretreatment with IL-6 siRNA improved CLP induced septic mice survival. Furthermore, the IL-6 level was down-regulated and the transcription factors ROR-γt and PU.1 were up-regulated by IL-6 siRNA at late sepsis. The results presented herein also suggest that IL-6 siRNA could be a potential molecular therapeutic strategy for the treatment of sepsis.
Laboratory of Cell Biology, Ajou University Institute for Medical Sciences, Suwon 443‐721, Republic of Korea.
A K M
AK
Mostafa Anower
Ju A
JA
Shim
Bunsoon
B
Choi
Seonghyang
S
Sohn
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001806:Blood Urea Nitrogen; D002432:Cecum / Q000187:drug effects / Q000293:injuries* / Q000382:microbiology*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D008026:Ligation / Q000009:adverse effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011677:Punctures / Q000009:adverse effects*; D034741:RNA, Small Interfering / Q000235:genetics*; D011951:Receptors, Complement / Q000235:genetics; D018805:Sepsis / Q000209:etiology / Q000378:metabolism / Q000382:microbiology; D016019:Survival Analysis; D015996:Survival Rate; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D000900:Anti-Bacterial Agents; D015850:Interleukin-6; D034741:RNA, Small Interfering; D011951:Receptors, Complement; D000410:Alanine Transaminase