Dataset Information

MicroRNA 339 down-regulates ?-opioid receptor at the post-transcriptional level in response to opioid treatment.

ABSTRACT: ?-Opioid receptor (MOR) level is directly related to the function of opioid drugs, such as morphine and fentanyl. Although agonist treatment generally does not affect transcription of mor, previous studies suggest that morphine can affect the translation efficiency of MOR transcript via microRNAs (miRNAs). On the basis of miRNA microarray analyses of the hippocampal total RNA isolated from mice chronically treated with ?-opioid agonists, we found a miRNA (miR-339-3p) that was consistently and specifically increased by morphine (2-fold) and by fentanyl (3.8-fold). miR-339-3p bound to the MOR 3'-UTR and specifically suppressed reporter activity. Suppression was blunted by adding miR-339-3p inhibitor or mutating the miR-339-3p target site. In cells endogenously expressing MOR, miR-339-3p inhibited the production of MOR protein by destabilizing MOR mRNA. Up-regulation of miR-339-3p by fentanyl (EC(50)=0.75 nM) resulted from an increase in primary miRNA transcript. Mapping of the miR-339-3p primary RNA and its promoter revealed that the primary miR-339-3p was embedded in a noncoding 3'-UTR region of an unknown host gene and was coregulated by the host promoter. The identified promoter was activated by opioid agonist treatment (10 nM fentanyl or 10 ?M morphine), a specific effect blocked by the opioid antagonist naloxone (10 ?M). Taken together, these results suggest that miR-339-3p may serve as a negative feedback modulator of MOR signals by regulating intracellular MOR biosynthesis.

SUBMITTER: Wu Q

PROVIDER: S-EPMC3545525 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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MicroRNA 339 down-regulates μ-opioid receptor at the post-transcriptional level in response to opioid treatment.

Wu Qifang Q Hwang Cheol Kyu CK Zheng Hui H Wagley Yadav Y Lin Hong-Yiou HY Kim Do Kyung DK Law Ping-Yee PY Loh Horace H HH Wei Li-Na LN

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20121019 2

μ-Opioid receptor (MOR) level is directly related to the function of opioid drugs, such as morphine and fentanyl. Although agonist treatment generally does not affect transcription of mor, previous studies suggest that morphine can affect the translation efficiency of MOR transcript via microRNAs (miRNAs). On the basis of miRNA microarray analyses of the hippocampal total RNA isolated from mice chronically treated with μ-opioid agonists, we found a miRNA (miR-339-3p) that was consistently and sp ...[more]

PMID: 23085997

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Project description:INTRODUCTION:The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNF? and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. METHODS:SF lines were stimulated with either TNF?, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value <?0.05 was considered statistically significant. RESULTS:The stimulation of SF with IL6/sIL6R and TNF?, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNF? and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. CONCLUSIONS:These results point out to a highly orchestrated response to IL6 in TNF?-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells.

Dataset Information

MicroRNA 339 down-regulates ?-opioid receptor at the post-transcriptional level in response to opioid treatment.

Publications

MicroRNA 339 down-regulates μ-opioid receptor at the post-transcriptional level in response to opioid treatment.

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