Abstract
beta-Carotene has shown antioxidant and anti-inflammatory activities; however, its molecular mechanism has not been clearly defined. We examined in vitro and in vivo regulatory function of beta-carotene on the production of nitric oxide (NO) and PGE(2) as well as expression of inducible NO synthase (iNOS), cyclooxygenase-2, TNF-alpha, and IL-1beta. beta-Carotene inhibited the expression and production of these inflammatory mediators in both LPS-stimulated RAW264.7 cells and primary macrophages in a dose-dependent fashion as well as in LPS-administrated mice. Furthermore, this compound suppressed NF-kappaB activation and iNOS promoter activity in RAW264.7 cells stimulated with LPS. beta-Carotene blocked nuclear translocation of NF-kappaB p65 subunit, which correlated with its inhibitory effect on IkappaBalpha phosphorylation and degradation. This compound directly blocked the intracellular accumulation of reactive oxygen species in RAW264.7 cells stimulated with LPS as both the NADPH oxidase inhibitor diphenylene iodonium and antioxidant pyrrolidine dithiocarbamate did. The inhibition of NADPH oxidase also inhibited NO production, iNOS expression, and iNOS promoter activity. These results suggest that beta-carotene possesses anti-inflammatory activity by functioning as a potential inhibitor for redox-based NF-kappaB activation, probably due to its antioxidant activity.
Highlights
Macrophages play an important role in host defense against noxious substances and are involved in a variety of disease processes, including autoimmune diseases, infections, and inflammatory disorders (Pierce, 1990)
Inflammatory stimuli such as LPS and IFN-γ activate macrophages to produce a variety of pro-inflammatory cytokines such as TNF-α and IL-1β as well as other inflammatory mediators including PGE2 and nitric oxide (NO), which are synthesized by cyclooxygenase (COX) and inducible nitric oxide synthase, respectively
Antiinflammatory drugs and agents reduce the inflam matory response by suppressing the production of the inflammatory mediators and in turn block the initiation and progression of inflammation-associated diseases (Leach et al, 1998; Ritchlin et al, 2003). Expression of these cytokine and enzyme genes can be regulated by the activation of the transcription factor nuclear factor-kappa B (NF-κB), which is critically involved in several aspects of the pathogenesis of rheumatoid arthritis and other chronic inflammatory diseases (Makarov, 2000; Tak et al, 2001)
Summary
Macrophages play an important role in host defense against noxious substances and are involved in a variety of disease processes, including autoimmune diseases, infections, and inflammatory disorders (Pierce, 1990) Inflammatory stimuli such as LPS and IFN-γ activate macrophages to produce a variety of pro-inflammatory cytokines such as TNF-α and IL-1β as well as other inflammatory mediators including PGE2 and nitric oxide (NO), which are synthesized by cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS), respectively. Antiinflammatory drugs and agents reduce the inflam matory response by suppressing the production of the inflammatory mediators and in turn block the initiation and progression of inflammation-associated diseases (Leach et al, 1998; Ritchlin et al, 2003) Expression of these cytokine and enzyme genes can be regulated by the activation of the transcription factor nuclear factor-kappa B (NF-κB), which is critically involved in several aspects of the pathogenesis of rheumatoid arthritis and other chronic inflammatory diseases (Makarov, 2000; Tak et al, 2001). These results indicate that β-carotene possesses anti-inflammatory potential by suppressing inflammatory cytokines and modulators through the suppression of redox-based NF-κB activation
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