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Upregulation of Suppressor of Cytokine Signaling 3 in Microglia by Cinnamic Acid

[ Vol. 15 , Issue. 10 ]

Author(s):

Sudipta Chakrabarti, Malabendu Jana, Avik Roy and Kalipada Pahan*   Pages 894 - 904 ( 11 )

Abstract:


Background: Neuroinflammation plays an important role in the pathogenesis of various neurodegenerative diseases including Alzheimer’s disease (AD). Suppressor of cytokine signaling 3 (SOCS3) is an anti-inflammatory molecule that suppresses cytokine signaling and inflammatory gene expression in different cells including microglia.

Objective: The pathways through which SOCS3 could be upregulated are poorly described. Cinnamic acid is a metabolite of cinnamon, a natural compound that is being widely used all over the world as a spice or flavoring agent. Here, we examined if cinnamic acid could upregulate SOCS3 in microglia.

Method: Microglia and astroglia isolated from mouse brain as well as BV-2 microglial cells were treated with cinnamic acid followed by monitoring the level of SOCS3 and different proinflammatory molecules by RT-PCR and real-time PCR. To nail down the mechanism, we also performed ChIP analysis to monitore the recruitment of cAMP response element binding (CREB) to the socs3 gene promoter and carried out siRNA knockdown of CREB.

Results: Cinnamic acid upregulated the expression of SOCS3 mRNA and protein in mouse BV-2 microglial cells in dose- and time-dependent manner. Accordingly, cinnamic acid also increased the level of SOCS3 and suppressed the expression of inducible nitric oxide synthase and proinflammatory cytokines (TNFα, IL-1β and IL-6) in LPSstimulated BV-2 microglial cells. Similar to BV-2 microglial cells, cinnamic acid also increased the expression of SOCS3 in primary mouse microglia and astrocytes. We have seen that cAMP response element is present in the promoter of socs3 gene, that cinnamic acid induces the activation of CREB, that siRNA knockdown of CREB abrogates cinnamic acid-mediated upregulation of SOCS3, and that cinnamic acid treatment leads to the recruitment of CREB to the socs3 gene.

Conclusions: These studies suggest that cinnamic acid upregulates the expression of SOCS3 in glial cells via CREB pathway, which may be of importance in neuroinflammatory and neurodegenerative disorders.

Keywords:

Cinnamic acid, glial cells, SOCS3, CREB, neuroinflammation, microglial cells.

Affiliation:

Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL-60612, Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL-60612, Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL-60612, Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL-60612



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