MicroRNA-204-5p suppresses IL6-mediated inflammatory response and chemokine generation in HK-2 renal tubular epithelial cells by targeting IL6R

During the pathogenetic process of varied kidney diseases, renal tubules are the major sites in response to detrimental insults, including pro-inflammatory stimuli. MicroRNA-204-5p (miR-204-5p) can be detected in the renal tubular epithelial cells in the normal kidney; its expression, however, is downregulated in the kidney with pathological changes. This study aimed to investigate the role of miR-204-5p in interleukin 6 (IL6) mediated inflammatory response and chemokine production in HK-2 renal tubular cells. In HK-2 cells, the expression of miR-204-5p was downregulated in response to exogenous pro-inflammatory stimulus, tumor necrosis factor [alpha] (TNF[alpha]), or IL1[beta], while that of IL6 receptor [alpha] (IL6R) was upregulated. Dual-luciferase results confirmed that miRNA-204-5p directly targeted IL6R. In addition to suppressing IL6R expression, miRNA-204-5p agomir also inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in HK-2 cells exposed to exogenous IL6. Further, miRNA-204-5p suppressed the overproduction of pro-inflammatory mediators (cyclooxygenase 2 and prostaglandin [E.sub.2]) and chemokines (C-C motif chemokine ligand 2 and C-X-C motif chemokine ligand 8). The anti-inflammatory effects of miRNA-204-5p were attenuated when IL6R was reexpressed in HK-2 cells. Collectively, our study reveals that miR-204-5p inhibits the inflammation and chemokine generation in renal tubular epithelial cells by modulating the IL6/IL6R axis. Key words: microRNA-204-5p, IL6R, renal tubular epithelial cells, inflammation, chemokine generation. Durant le processus pathogenique qui mene au developpement de diverses maladies renales, les tubules sont les principaux sites endommages par differentes agressions, y compris par les stimulus pro-inflammatoires. Le microARN-204-5p (miR-204-5p) peut etre detecte dans les cellules epitheliales tubulaires renales du rein normal, mais son expression est toutefois regulee a la baisse dans le rein pathologique. Cette etude visait a examiner le role du miR-204-5p sur la reponse inflammatoire mediee par l'interleukine-6 (IL6) et la production de chimiokines chez les cellules tubulaires renales HK-2. L'expression du miR-204-5p etait regulee a la baisse dans ces cellules en reponse a un stimulus pro-inflammatoire exogene, soit le facteur de necrose tumorale [alpha] (TNF[alpha]) ou l'IL1[beta], alors que le recepteur de l'IL6 [alpha] (IL6R) etait regule a la hausse. Les resultats d'un dosage double de la luciferase confirmaient que le miR-204-5p ciblait directement l'IL6R. En plus de supprimer l'expression de l'IL6R, un miR-204-5p synthetique (agomir) inhibait aussi la phosphorylation de STAT3 chez les cellules HK-2 exposees a l'IL6 exogene. En outre, le miR-204-5p supprimait la surproduction de mediateurs (cyclooxygenase 2 et prostaglandine E2) et de chimiokines (CCL2 et CXCL8) pro-inflammatoires. Les effets anti-inflammatoires du miR-204-5p etaient attenues lorsque l'IL6R etait reexprime dans les cellules HK-2. Dans son ensemble, l'etude des auteurs revele que le miR-204-5p inhibe l'inflammation et la production de chimiokines dans les cellules epitheliales tubulaires renales en modulant l'axe IL6/IL6R. [Traduit par la Redaction] Mots-cles: microARN-204-5p, IL6R, cellules epitheliales tubulaires renales, inflammation, production de chimiokine.
Introduction MicroRNAs (miRNAs) are a group of small noncoding RNAs (19-23 nt) that regulate gene expression. As epigenetic regulators, miRNAs participate not only in the development and homeostasis of the [...]