title: 22(R)-hydroxycholesterol induces HuR-dependent MAP kinase phosphatase-1 expression via mGluR5-mediated Ca(2+)/PKCα signaling.
abstract: MAP kinase phosphatase (MKP)-1 plays a pivotal role in controlling MAP kinase (MAPK)-dependent (patho) physiological processes. Although MKP-1 gene expression is tightly regulated at multiple levels, the underlying mechanistic details remain largely unknown. In this study, we demonstrate that MKP-1 expression is regulated at the post-transcriptional level by 22(R)-hydroxycholesterol [22(R)-HC] through a novel mechanism. 22(R)-HC induces Hu antigen R (HuR) phosphorylation, cytoplasmic translocation and binding to MKP-1 mRNA, resulting in stabilization of MKP-1 mRNA. The resulting increase in MKP-1 leads to suppression of JNK-mediated inflammatory responses in brain astrocytes. We further demonstrate that 22(R)-HC-induced phosphorylation of nuclear HuR is mediated by PKCα, which is activated in the cytosol by increases in intracellular Ca(2+) levels mediated by the phospholipase C/inositol 1,4,5-triphosphate receptor (PLC/IP3R) pathway and translocates from cytoplasm to nucleus. In addition, pharmacological interventions reveal that metabotropic glutamate receptor5 (mGluR5) is responsible for the increases in intracellular Ca(2+) that underlie these actions of 22(R)-HC. Collectively, our findings identify a novel anti-inflammatory mechanism of 22(R)-HC, which acts through PKCα-mediated cytoplasmic shuttling of HuR to post-transcriptionally regulate MKP-1 expression. These findings provide an experimental basis for the development of a RNA-targeted therapeutic agent to control MAPK-dependent inflammatory responses.
authors.affiliation: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 16499, Korea.
authors.forename: Hyunmi
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 16499, Korea. Electronic address: joohongwoo@hanmail.net.
authors.forename: Joo Hong
authors.initials: JH
authors.lastname: Woo
authors.affiliation: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 16499, Korea.
authors.forename: Jee Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 16499, Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Joe
authors.affiliation: Department of Pharmacology and Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 16499, Korea. Electronic address: jouilo@aumc.ac.kr.
authors.forename: Ilo
authors.initials: I
authors.lastname: Jou
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics* / Q000378:metabolism; D000067780:ELAV-Like Protein 1 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006888:Hydroxycholesterols / Q000494:pharmacology*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D011485:Protein Binding; D051571:Protein Kinase C-alpha / Q000235:genetics* / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism
chemical_list: D000067780:ELAV-Like Protein 1; C000593998:Elavl1 protein, rat; C578937:Grm5 protein, rat; D006888:Hydroxycholesterols; D053496:Inositol 1,4,5-Trisphosphate Receptors; C488910:Itpr1 protein, rat; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; C003585:22-hydroxycholesterol; D051571:Protein Kinase C-alpha; D048670:MAP Kinase Kinase 4; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D010738:Type C Phospholipases; D002118:Calcium
keywords: 22(R)-hydroxycholesterol; HuR; MKP-1; PKCα; Post-transcriptional regulation; mGluR5