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5, 8, 11, 14-eicosatetraynoic Acid Suppresses CCL2/MCP-1 Expression in IFN-γ-stimulated Astrocytes by Increasing MAPK phosphatase-1 mRNA Stability

5, 8, 11, 14-eicosatetraynoic Acid Suppresses CCL2/MCP-1 Expression in IFN-γ-stimulated Astrocytes by Increasing MAPK phosphatase-1 mRNA Stability

Jee Hoon Lee, Hyunmi Kim, Joo Hong Woo, Eun-hye Joe, Ilo Jou

J Neuroinflammation. 2012 Feb 18;9:34.

PMID: 22339770

Abstract:

Background:
The peroxisome proliferator-activated receptor (PPAR)-α activator, 5,8,11,14-eicosatetraynoic acid (ETYA), is an arachidonic acid analog. It is reported to inhibit up-regulation of pro-inflammatory genes; however, its underlying mechanism of action is largely unknown. In the present study, we focused on the inhibitory action of ETYA on the expression of the chemokine, CCL2/MCP-1, which plays a key role in the initiation and progression of inflammation.
Methods:
To determine the effect of ETYA, primary cultured rat astrocytes and microglia were stimulated with IFN-γ in the presence of ETYA and then, expression of CCL2/MCP-1 and MAPK phosphatase (MKP-1) were determined using RT-PCR and ELISA. MKP-1 mRNA stability was evaluated by treating actinomycin D. The effect of MKP-1 and human antigen R (HuR) was analyzed by using specific siRNA transfection system. The localization of HuR was analyzed by immunocytochemistry and subcellular fractionation experiment.
Results:
We found that ETYA suppressed CCL2/MCP-1 transcription and secretion of CCL2/MCP-1 protein through up-regulation of MKP-1mRNA levels, resulting in suppression of c-Jun N-terminal kinase (JNK) phosphorylation and activator protein 1 (AP1) activity in IFN-γ-stimulated brain glial cells. Moreover, these effects of ETYA were independent of PPAR-α. Experiments using actinomycin D revealed that the ETYA-induced increase in MKP-1 mRNA levels reflected an increase in transcript stability. Knockdown experiments using small interfering RNA demonstrated that this increase in MKP-1 mRNA stability depended on HuR, an RNA-binding protein known to promote enhanced mRNA stability. Furthermore, ETYA-induced, HuR-mediated mRNA stabilization resulted from HuR-MKP-1 nucleocytoplasmic translocation, which served to protect MKP-1 mRNA from the mRNA degradation machinery.
Conclusion:
ETYA induces MKP-1 through HuR at the post-transcriptional level in a receptor-independent manner. The mechanism revealed here suggests eicosanoids as potential therapeutic modulators of inflammation that act through a novel target.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1191851-A	5,8,11,14-Eicosatetraynoic acid		1191-85-1	Price

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