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

Abstract

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.