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 IκB kinase (IKK) β/nuclear factor-κB (NF-κB) 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-κB activation and sequentially suppresses its downstream inducible nitric oxide synthase, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) transcription and supernatant nitric oxide and IL-6 levels by inhibiting IKKβ (IC50 ≈ 11.79μM). But in the meantime, rhein enhances the activity of caspase-1 by inhibiting intracellular (in situ) IKKβ, in turn increasing the IL-1β 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 IKKβ inhibition that rhein significantly enhances TNF-α secretion and phagocytosis in macrophages with or without LPS. These results indicate that rhein exerts anti- and proinflammatory activities by targeting IKKβ inhibition, providing a molecular mechanism for the unanticipated role of rhein in macrophages. Furthermore, our study also highlights the potential complications of IKKβ inhibitor (e.g., rhein, diacerein, etc.) application in inflammation disorders, for the overall effects of IKKβ inhibition in various organ systems and disease processes are not easily predictable under all circumstances.
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
Yuan
Y
Gao
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
Xi
X
Chen
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
Lei
L
Fang
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
Fen
F
Liu
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
Runlan
R
Cai
Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China. Electronic address: pengchengchengdu@126.com.
Cheng
C
Peng
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China. Electronic address: yqi@implad.ac.cn.
Yun
Y
Qi
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D000880:Anthraquinones; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D051550:I-kappa B Kinase; C020491:rhein
Caspase-1; Free radicals; IκB kinase β; Lipopolysaccharide; Macrophages; Nuclear factor-κB; Rhein; Superoxide anion