Abstract
Background Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by sacroiliitis and spinal rigidity of the axial joints. The role of oxidative stress and increased proinflammatory cytokines is well documented in AS pathogenesis. Punicalagin (2,3-hexahydroxydiphenoyl-gallagyl-D-glucose), an ellagitannin widely present in pomegranates, is found to exhibit potent anti-inflammatory, antiproliferative, and antioxidative effects. The present study was undertaken to investigate the effects of punicalagin in a rodent model of AS. Methods BALB/c mice induced spondylitis were sacrificed 24 h after the last injection of proteoglycan extract. Histological scoring was done to assess the degree of the disease. The expression of JAK2/STAT3 proteins and proteins of the nuclear factor-κB (NF-κB) pathway was determined by immunoblotting. Serum levels of inflammatory mediators—TNF-α, IL-1β, IL-6, IL-17A, and IL-23—were assessed. Levels of lipid peroxidation and reactive oxygen species (ROS) were quantified. Antioxidant status as a measure of activities of antioxidant enzymes—catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD)—was determined. Results Punicalagin effectively improved antioxidant status and decreased lipid peroxidation, ROS production, and serum levels of inflammatory mediators. NF-κB pathway and JAK2/STAT3 signaling were significantly (p < 0.05) downregulated. Punicalagin effectively regulated the production of cytokines by the Th17 cells and the IL-17A/IL-23 axis. Conclusion The observations suggest that punicalagin exerts a protective role in AS via reducing oxidative stress and regulating NF-κB/TH17/JAK2/STAT3 signal. Punicalagin thus could be explored further as a potent candidate compound in the treatment of AS.
Highlights
Ankylosing spondylitis (AS) is a chronic, progressive inflammatory condition with a global prevalence rate of 0.1-1.4% [1]
Of all the interleukins secreted by Th17 cells, IL-1β, IL-17, and IL-26 are most specific to Th17 cell response [2, 8,9,10,11]
The JAK2/tyrosine kinase 2 (TYK2)-STAT3 signal is found to be involved in IL-23mediated regulation of Th17 cells
Summary
Ankylosing spondylitis (AS) is a chronic, progressive inflammatory condition with a global prevalence rate of 0.1-1.4% [1]. Studies have reported disturbed cytokine networks and elevated reactive oxygen species (ROS) levels in AS [5,6,7]. Janus kinases 1/2/3 (JAK1/2/3) and tyrosine kinase 2 (TYK2), along with activators of transcription (STAT) signaling and signal transducers, are the major factors in the transmission of pro- and anti-inflammatory cytokine signals [17, 18]. The JAK2/TYK2-STAT3 signal is found to be involved in IL-23mediated regulation of Th17 cells. Cells as neutrophils produce raised levels of ROS that lead to oxidative stress. Punicalagin effectively improved antioxidant status and decreased lipid peroxidation, ROS production, and serum levels of inflammatory mediators. The observations suggest that punicalagin exerts a protective role in AS via reducing oxidative stress and regulating NF-κB/TH17/JAK2/STAT3 signal. Punicalagin could be explored further as a potent candidate compound in the treatment of AS
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