The synthetic triterpenoid, CDDO-Me, modulates the proinflammatory response to in vivo lipopolysaccharide challenge.
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.
Auletta
Jeffery J
JJ
Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio, USA. jeffery.auletta@case.edu
Alabran
Jennifer L
JL
Kim
Byung-Gyu
BG
Meyer
Colin J
CJ
Letterio
John J
JJ
D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D056747:Immunomodulation; D007249:Inflammation; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D020381:Interleukin-17 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D013154:Spleen; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D018836:Inflammation Mediators; D020381:Interleukin-17; D008070:Lipopolysaccharides; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D006419:Heme Oxygenase (Decyclizing)