title: Cecal ligation and puncture sepsis is associated with attenuated expression of adenylyl cyclase 9 and increased miR142-3p.
abstract: The host inflammatory response in sepsis may be resolved by endogenous anti-inflammatory immune cell responses, avoiding fatal pathogenesis, organ injury, and death. The intracellular signaling mediator cyclic 3'5'-adenosine monophosphate is a potent modulator of inflammatory responses and initiates the polarization of immune cells in a direction that suppresses inflammatory activation. Cyclic 3'5'-adenosine monophosphate is enzymatically produced by adenylyl cyclases (ACs). The expression of ACs is previously shown to be reduced in rat organs after in vivo endotoxemia, concurrent with the progressing systemic inflammation. In the present study, tissue AC gene expression and regulation are explored in a rat model of cecal ligation and puncture (CLP) sepsis. Eighteen hours after CLP operation, expression of several AC isoforms in the liver, spleen, and kidney was reduced, significantly so for AC9 in all tissues. AC9 expression is regulated by the microRNA miR142-3p in T cells. When microRNA was extracted and amplified for miR142-3p expression, it was increasingly expressed 18 h after CLP. A correlation between increased miR142-3p and decreased AC9 expression was found in the liver, kidney, and spleen, and when hepatocytes, Kupffer cells (KCs), and liver sinusoidal endothelial cells were isolated after CLP, reduced AC expression and increased miR142-3p expression were found in KCs and liver sinusoidal endothelial cells. Transfecting a miR142-3p inhibitor probe in rat KCs abolished LPS-mediated AC9 inhibition in vitro. These results indicate that CLP leads to miR142-3p-mediated AC9 reduction in liver macrophages, which may further limit cyclic 3'5'-adenosine monophosphate signaling and the ability of macrophages to resolve the proinflammatory response.
authors.affiliation: Institute for Surgical Research, Oslo University Hospital-Rikshospitalet, University of Oslo, Oslo, Norway.
authors.forename: Petter K
authors.initials: PK
authors.lastname: Risøe
authors.forename: Una
authors.initials: U
authors.lastname: Ryg
authors.forename: Yun Yong
authors.initials: YY
authors.lastname: Wang
authors.forename: Arkady
authors.initials: A
authors.lastname: Rutkovskiy
authors.forename: Bård
authors.initials: B
authors.lastname: Smedsrød
authors.forename: Guro
authors.initials: G
authors.lastname: Valen
authors.forename: Maria K
authors.initials: MK
authors.lastname: Dahle
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002432:Cecum / Q000293:injuries*; D002478:Cells, Cultured; D022781:Hepatocytes / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011677:Punctures; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D000262:Adenylyl Cyclases