Rhein exerts pro- and anti-inflammatory actions by targeting IKKβ inhibition in LPS-activated macrophages

Because steroids and cyclooxygenase inhibitors may cause serious side effects, the I kappa B kinase (IKK) beta/nuclear factor-kappa B (NF-kappa B) system has become an intriguing candidate anti-inflammatory target. Rhein, the active metabolite of diacerein, possesses anti-inflammatory ability with a gastrointestinal protective effect. However, in a preliminary study, we accidentally found that rhein showed both anti- and proinflammatory activities in lipopolysaccharide (LPS)-activated macrophages. Thus, in this study, we explored the underlying molecular mechanisms of the dual effects of rhein. In LPS-activated macrophages, rhein inhibits NF-kappa B activation and sequentially suppresses its downstream inducible nitric oxide synthase, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta) transcription and supernatant nitric oxide and IL-6 levels by inhibiting IKK beta (IC50 approximate to 11.79 mu M). But in the meantime, rhein enhances the activity of caspase-1 by inhibiting intracellular (in situ) IKK beta, in turn increasing the IL-1 beta and high-mobility-group box 1 release, which can be amplified by rhein's reductive effect on intracellular superoxide anion. Unexpectedly, it is because of IKK beta inhibition that rhein significantly enhances TNF-alpha secretion and phagocytosis in macrophages with or without LPS. These results indicate that rhein exerts anti- and proinflammatory activities by targeting IKK beta inhibition, providing a molecular mechanism for the unanticipated role of rhein in macrophages. Furthermore, our study also highlights the potential complications of IKK beta inhibitor (e.g., rhein, diacerein, etc.) application in inflammation disorders, for the overall effects of IKK beta inhibition in various organ systems and disease processes are not easily predictable under all circumstances. (C) 2014 Elsevier Inc. All rights reserved.