title: Role of miR-146a in regulation of the acute inflammatory response to monosodium urate crystals.
abstract: OBJECTIVE
  MicroRNAs (miRNA) are small non-coding RNAs that function as post-transcriptional repressors of gene expression. We hypothesised that miRNA regulate gene expression of proinflammatory cytokines in response to monosodium urate (MSU) crystals.
  
  
  METHODS
  We stimulated human monocytic THP-1 cells with MSU crystals and examined miRNA and proinflammatory cytokine gene expression. The effects of miR-146a overexpression were examined by transfecting THP-1 cells with miR-146a precursor. miR-146a expression was examined in the urate peritonitis model, in peripheral blood mononuclear cells from people with gout and control participants, and in gouty tophus samples.
  
  
  RESULTS
  MSU crystals increased miR-146a expression in THP-1 cells, but not other miRNA implicated in interleukin (IL)-1β regulation. Overexpression of miR-146a expression reduced MSU crystal-induced IL-1β, tumour necrosis factor-α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and IL-8 gene expression. In the urate peritonitis model, reduced miR-146a expression was observed during the acute inflammatory response to MSU crystal injection. In people with intercritical gout, peripheral blood mononuclear cells expressed significantly higher levels of miR-146a, compared with normouricaemic and hyperuricaemic control participants and those with acute gout flares. Expression of miR-146a was also observed in all tophus samples.
  
  
  CONCLUSIONS
  Collectively, these data suggest that miR-146a is a transcriptional brake that is lost during the acute inflammatory response to MSU crystals.
authors: Bone and Joint Research Group, Department of Medicine, University of Auckland, Auckland, New Zealand.
authors: Nicola
authors: N
authors: Dalbeth
authors: Bone and Joint Research Group, Department of Medicine, University of Auckland, Auckland, New Zealand.
authors: Bregina
authors: B
authors: Pool
authors: Malaghan Institute for Medical Research, Wellington, New Zealand.
authors: Odette M
authors: OM
authors: Shaw
authors: Malaghan Institute for Medical Research, Wellington, New Zealand.
authors: Jacquie L
authors: JL
authors: Harper
authors: Bone and Joint Research Group, Department of Medicine, University of Auckland, Auckland, New Zealand.
authors: Paul
authors: P
authors: Tan
authors: Bone and Joint Research Group, Department of Medicine, University of Auckland, Auckland, New Zealand.
authors: Christopher
authors: C
authors: Franklin
authors: Bone and Joint Research Group, Department of Medicine, University of Auckland, Auckland, New Zealand.
authors: Meaghan E
authors: ME
authors: House
authors: Bone and Joint Research Group, Department of Medicine, University of Auckland, Auckland, New Zealand.
authors: Jillian
authors: J
authors: Cornish
authors: Bone and Joint Research Group, Department of Medicine, University of Auckland, Auckland, New Zealand.
authors: Dorit
authors: D
authors: Naot
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016022:Case-Control Studies; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006073:Gout / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000187:drug effects / Q000235:genetics*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014527:Uric Acid / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D053583:Interleukin-1beta; D016209:Interleukin-8; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha; D014527:Uric Acid
keywords: Cytokines; Gout; Inflammation