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Published on: January 30, 2014
Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression
Kavon Rezai-Zadeh1, Jared Ehrhart, Yun Bai
1Silver Child Development Center, Department of Psychiatry and Behavioral Medicine, College of Medicine, University of South Florida, Tampa, FL 33612, USA. krezaiza@health.usf.edu
Background:
It is well known that most neurodegenerative diseases are associated with microglia-mediated inflammation. Our previous research demonstrates that the CD40 signaling is critically involved in microglia-related immune responses in the brain. For example, it is well known that the activation of the signal transducer and activator of transcription (STAT) signaling pathway plays a central role in interferon-gamma (IFN-gamma)-induced microglial CD40 expression. We and others have previously reported that microglial CD40 expression is significantly induced by IFN-gamma and amyloid-beta (A beta) peptide. Recent studies have shown that certain flavonoids possess anti-inflammatory and neuroprotective properties distinct from their well-known anti-oxidant effects. In particular, flavonoids, apigenin and luteolin have been found to be effective CD40 immunomodulators.
Methods:
Cultured microglia, both N9 and primary derived lines, were treated with flavonoids in the presence of IFN-gamma and/or CD40 ligation to assess any anti-inflammatory effects and/or mechanisms. CD40 expression on microglia was analyzed by fluorescence activated cell sorting (FACS). Anti-inflammatory effects and mechanisms were confirmed by ELISA for interleukin-6 (IL-6) and TNF-alpha, lactate dehydrogenase (LDH) assay, and STAT1 Western blotting.
Results:
Apigenin and luteolin concentration-dependently suppressed IFN-gamma-induced CD40 expression. Apigenin and luteolin also suppressed microglial TNF-alpha and IL-6 production stimulated by IFN-gamma challenge in the presence of CD40 ligation. In addition, apigenin and luteolin markedly inhibited IFN-gamma-induced phosphorylation of STAT1 with little impact on cell survival.
Conclusion:
Our findings provide further support for apigenin and luteolin's anti-inflammatory effects and suggest that these flavonoids may have neuroprotective/disease-modifying properties in various neurodegenerative disorders, including Alzheimer's disease (AD).
Insights
Flavonoids apigenin and luteolin reduce neuroinflammation by suppressing microglial CD40 expression and STAT1 activation. These findings suggest potential neuroprotective effects for neurodegenerative diseases like Alzheimer's disease.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Neurodegenerative diseases involve microglia-mediated inflammation.
- CD40 signaling is crucial in brain immune responses.
- Flavonoids apigenin and luteolin show anti-inflammatory potential.
Purpose of the Study:
- To investigate the immunomodulatory effects of apigenin and luteolin on microglia.
- To explore their impact on CD40 expression and related inflammatory pathways.
Main Methods:
- Cultured microglia (N9 and primary) treated with flavonoids, interferon-gamma (IFN-gamma), and CD40 ligation.
- Analysis of CD40 expression via fluorescence-activated cell sorting (FACS).
- Assessed anti-inflammatory effects using ELISA (IL-6, TNF-alpha), LDH assay, and Western blotting (STAT1 phosphorylation).
Main Results:
- Apigenin and luteolin suppressed IFN-gamma-induced CD40 expression concentration-dependently.
- Flavonoids reduced microglial TNF-alpha and IL-6 production.
- Apigenin and luteolin inhibited IFN-gamma-induced STAT1 phosphorylation without affecting cell survival.
Conclusions:
- Apigenin and luteolin demonstrate significant anti-inflammatory effects on microglia.
- These flavonoids may offer neuroprotection and disease modification in neurodegenerative disorders, including Alzheimer's disease.
