Abstract
Schisandrin A (Sch A) and schisandrin B (Sch B) are active components of Schisandrae Fructus. We compared the biochemical mechanism underlying the anti-inflammatory action of Sch A and Sch B, using cultured lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and concanavalin (ConA)-stimulated mouse splenocytes. Pre-incubation with Sch A or Sch B produced an anti-inflammatory action in LPS-stimulated RAW264.7 cells, as evidenced by the inhibition of the pro-inflammatory c-Jun N-terminal kinases/p38 kinase/nuclear factor-κB signaling pathway as well as the suppression of various pro-inflammatory cytokines and effectors, with the extent of inhibition by Sch A being more pronounced. The greater activity of Sch A in anti-inflammatory response was associated with a greater decrease in cellular reduced glutathione (GSH) level and a greater increase in glutathione S-transferase activity than corresponding changes produced by Sch B. However, upon incubation, only Sch B resulted in the activation of the nuclear factor (erythroid-derived 2)-like factor 2 and the induction of a significant increase in the expression of thioredoxin (TRX) in RAW264.7 cells. The Sch B-induced increase in TRX expression was associated with the suppression of pro-inflammatory cytokines and effectors in LPS-stimulated macrophages. Studies in a mouse model of inflammation (carrageenan-induced paw edema) indicated that while long-term treatment with either Sch A or Sch B suppressed the extent of paw edema, only acute treatment with Sch A produced a significant degree of inhibition on the inflammatory response. Although only Sch A decreased the cellular GSH level and suppressed the release of pro-inflammatory cytokines and cell proliferation in ConA-simulated splenocytes in vitro, both Sch A and Sch B treatments, while not altering cellular GSH levels, suppressed ConA-stimulated splenocyte proliferation ex vivo. These results suggest that Sch A and Sch B may act differentially on activating GST/ depleting cellular GSH and inducing an antioxidant response involved in their anti-inflammatory actions.
Highlights
The inflammatory response, as an integral part of innate immunity, enables the removal of pathogens and the clearance of injured cells by means of a complex interplay involving resident immune cells and patrolling immune cells via a series of biochemical events [1]
We examined the effects of Schisandrin A (Sch A) and schisandrin B (Sch B) on the proinflammatory signal transduction pathway (JNK1/2, p38 and NK-κB), on pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and on interleukin 6 (IL6)] and inflammatory effectors [inducible nitric oxide synthase, nitric oxide, cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2)] in LPS-activated RAW264.7 macrophages (Fig 2)
The anti-inflammatory action produced by Sch A and Sch B was associated with their ability to increase glutathione S-transferase (GST) activity and decrease cellular GSH level in macrophages, with the degree of stimulation/depletion produced by Sch A being more pronounced
Summary
The inflammatory response, as an integral part of innate immunity, enables the removal of pathogens and the clearance of injured cells by means of a complex interplay involving resident immune cells (resident macrophages) and patrolling immune cells (monocytes/macrophages, natural killer cells and neutrophils, etc) via a series of biochemical events [1]. Recent experimental evidence has suggested that the increased production of reactive oxygen species in T lymphocytes can alter cellular signaling transduction pathways, such as the modulation of T cell receptor signaling, the activation of the Src homology region 2 domain-containing phosphatase-1 (SHP-1) and the inactivation of tyrosine-specific protein phosphatase (PTPase) activities, with the resultant immunosenescence and other adverse effects [11]. In this regard, the activation of an antioxidant response, which counteracts oxidative stress, is likely to produce a beneficial effect against inflammation. The search for antiinflammatory agents, those with the ability to induce a Nrfs-mediated antioxidant response, is urgently in need
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