The Synthetic Triterpenoid, CDDO-Me, Modulates the Proinflammatory Response to In Vivo Lipopolysaccharide Challenge

被引:27
作者
Auletta, Jeffery J. [1 ,2 ,3 ]
Alabran, Jennifer L. [1 ]
Kim, Byung-Gyu [1 ]
Meyer, Colin J. [4 ]
Letterio, John J. [1 ,2 ]
机构
[1] Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA
[3] Case Western Reserve Univ, Ctr Stem Cell & Regenerat Med, Cleveland, OH 44106 USA
[4] Reata Pharmaceut Inc, Irving, TX USA
基金
美国国家卫生研究院;
关键词
NITRIC-OXIDE PRODUCTION; REGULATORY T-CELLS; NF-KAPPA-B; ENDOTOXIN TOLERANCE; HEME OXYGENASE-1; MOUSE MACROPHAGES; IMMUNE-RESPONSE; 2-CYANO-3,12-DIOXOOLEAN-1,9-DIEN-28-OIC ACID; DIRECT INHIBITION; CARBON-MONOXIDE;
D O I
10.1089/jir.2009.0100
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The synthetic triterpenoid, CDDO-Me, has potent antiproliferative and antioxidant properties. However, its immunomodulatory effects in the context of LPS challenge are incompletely defined. Pretreatment with oral CDDO-Me significantly improved survival following lethal-dose LPS challenge in mice. To define this protection further, we measured effects of CDDO-Me pretreatment on splenocyte populations and cytokine production following LPS challenge, using low-level LPS pretreatment as an in vivo control for reducing cytokine production. Despite similar decreases in levels of LPS-inducible, circulating proinflammatory cytokines (IL-12p70, IFN-gamma, IL-6, IL-17, and IL-23) and increases in heme oxygenase 1 (HO-1) protein expression, low-dose LPS and CDDO-Me pretreatments markedly differed in their overall response profiles. Splenocytes from LPS-pretreated mice contained reduced numbers of dendritic cells, increased percentages of Th17 and T-regulatory cells, lower levels of TLR-inducible IL-6, and higher levels of TLR-inducible IL-10. In contrast, CDDO-Me protection against LPS challenge had no impact on absolute numbers or distribution of splenocyte subsets, despite attenuating in vivo induction of proinflammatory cytokines in an IL-10-independent manner. Together, these results suggest that CDDO-Me pretreatment uniquely confers protection against LPS challenge by modulating the in vivo immune response to LPS. Thus, CDDO-Me potentially represents a novel oral agent for use in LPS-mediated inflammatory diseases.
引用
收藏
页码:497 / 508
页数:12
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