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Regulation of TLR2 Expression by Prostaglandins in Brain Glia¹

Hee Jung Yoon^*, Sae-Bom Jeon^*,, In-Hoo Kim and Eun Jung Park^2,*

^* Immune and Cell Therapy Branch, National Cancer Center, Goyang, Korea; Neuroscience Graduate Program, School of Medicine, Ajou University, Suwon, Korea; and Molecular Imaging and Therapy Branch, National Cancer Center, Goyang, Korea

TLR have emerged as important primary sensors for diverse stimuli and are increasingly implicated in various diseases. However, the molecular mechanisms underlying the regulation of the TLR system remain poorly understood. In this study, we report that some PGs may control TLR-mediated inflammatory events through modulation of TLR2 expression in brain immune cells. We first found that 15-deoxy-12,14-PG J₂ (15d-PGJ₂) markedly altered the expression of TLR2 but not TLR4, TLR1, and TLR9 at the message and protein levels in activated glia. Down-regulation of TLR2 expression and downstream events of TLR2 activation, including phagocytosis by 15d-PGJ₂, were also observed in cells treated with representative TLR2 ligands such as lipoteichoic acid and Pam₃CSK₄. We further revealed that certain 15d-PGJ₂-related PGs such as 15d-PGD₂ and PGD₂ also suppressed the ligand-stimulated increase of TLR2 expression, whereas PGE₂ and arachidonic acids did not. Interestingly, TLR2 expression was down-regulated even when such PGs were added at several hours after stimulator treatment. These findings appear to be independent of peroxisome proliferator-activated receptor and D prostanoid receptors (DPs) because potent synthetic peroxisome proliferator-activated receptor agonists, selective DP1 agonist, or DP2 agonist did not mimic the effects of such PGs on TLR2 expression. Taken together, our results suggest that 15d-PGJ₂, 15d-PGD₂, and PGD₂ may play notable roles as modulators of the TLR2-mediated inflammatory events, and provide new insight into the resolution of inflammation in the brain.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Cancer Center (0710320-1) and by KRF grant funded by the Korean Government (KRF-2005-041-E00103).

² Address correspondence and reprint requests to Dr. Eun Jung Park, Immune and Cell Therapy Branch, National Cancer Center, Goyang, 410-351, Korea. E-mail address: ejpark{at}ncc.re.kr

³ Abbreviations used in this paper: SOCS, suppressor of cytokine signaling; DP, D prostanoid receptor; COX, cyclooxygenase; 15d-PGJ₂, 15-deoxy-12,14-PG J₂; PPAR, peroxisome proliferator-activated receptor; LTA, lipoteichoic acid; iNOS, inducible NO synthase; DAPI, 4',6'-diamidino-2-phenylindole hydrochloride.