title: IL-1 receptor regulates microRNA-135b expression in a negative feedback mechanism during cigarette smoke-induced inflammation.
abstract: Although microRNA-135b (miR-135b) is known to be associated with cancer, with recent work showing that it is massively induced in the pulmonary tissues of mice challenged with nanoparticles suggests a critical role for this microRNA in mediating inflammatory response. In this study, we investigated the expression and function of miR-135b in mice exposed to cigarette smoke or nontypeable Haemophilus influenzae (NTHi). Exposure to both cigarette smoke and NTHi elicited robust lung inflammation, but increased miR-135b expression was observed only in the lungs of cigarette smoke-exposed mice. Using IL-1R 1 knockout mice, we show that miR-135b expression is IL-1R1 dependent. A series of in vitro experiments confirmed the role of IL-1R1 in regulating miR-135b expression. In vitro activation of the IL-1R1 pathway in mouse embryonic fibroblast (NIH3T3) and lung epithelial (FE1) cells resulted in increased miR-135b, which was blocked by IL-1R1 antagonists or small interfering RNA-mediated silencing of IL-1R1 expression. Overexpression of mature miR-135b in NIH3T3 cells (pEGP-mmu-mir-135b) resulted in the suppression of endogenous levels of IL-1R1 expression. pEGP-mmu-miR-135b cells transiently transfected with luciferase reporter vector containing the 3'UTR of mouse IL-1R1 showed reduced luciferase activity. Finally, we demonstrate that miR-135b targets IL-1-stimulated activation of Caspase-1, the IL-1R1 downstream activator of IL-1β leading to suppressed synthesis of the active form of IL-1β protein. These results suggest that miR-135b expression during cigarette smoke-induced inflammation is regulated by IL-1R1 in a regulatory feedback mechanism to resolve inflammation.
authors: Environmental and Radiation Health Sciences Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada. sabina.halappanavar@hc-sc.gc.ca
authors: Sabina
authors: S
authors: Halappanavar
authors: Jake
authors: J
authors: Nikota
authors: Dongmei
authors: D
authors: Wu
authors: Andrew
authors: A
authors: Williams
authors: Carole L
authors: CL
authors: Yauk
authors: Martin
authors: M
authors: Stampfli
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000209:etiology*; D018836:Inflammation Mediators / Q000378:metabolism; D053582:Interleukin-1alpha / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D041681:NIH 3T3 Cells; D017472:Receptors, Interleukin-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects
chemical_list: D020413:3' Untranslated Regions; D018836:Inflammation Mediators; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D035683:MicroRNAs; C549289:Mirn135 microRNA, mouse; D017472:Receptors, Interleukin-1; D020170:Caspase 1