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.