Calcineurin inhibitors down-regulate iNOS expression by destabilizing mRNA
Mari Hämäläinen1, Riku Korhonen, Eeva Moilanen
1The Immunopharmacology Research Group, University of Tampere Medical School and Tampere University Hospital, Research Unit, Tampere, Finland. mari.j.hamalainen@uta.fi
Abstract:
In inflammation, bacterial products and pro-inflammatory cytokines induce the expression of inducible nitric oxide synthase (iNOS) and formation of high amounts of nitric oxide (NO). In a number of inflammatory diseases NO has pro-inflammatory and cytotoxic effects. The aim of the present study was to investigate the effects of immunosuppressive drugs cyclosporin A (CsA), tacrolimus (FK-506) and pimecrolimus on NO production through iNOS pathway in activated macrophages and fibroblasts. Calcineurin inhibitors (CsA, FK-506 and pimecrolimus) inhibited NO production and iNOS expression in a concentration-dependent manner, CsA being more potent than FK-506 and pimecrolimus. No effect on the activation or activity of the transcription factors nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 1 (STAT-1) was found. CsA, FK-506 and pimecrolimus did not reduce iNOS mRNA levels when measured 6-8 h after the inflammatory stimulus, but significantly lower levels of iNOS mRNA were found after 24 h incubation. Also, in cells transfected with a luciferase gene under the control of 3' untranslated region (3'UTR) of iNOS, CsA reduced luciferase activity. In conclusion, the results suggest that calcineurin inhibitors cyclosporin A, tacrolimus (FK-506) and pimecrolimus inhibit iNOS expression and NO production in response to inflammatory stimuli by enhancing the decay of iNOS mRNA by a 3'UTR-dependent manner. The findings add our knowledge on the anti-inflammatory effects of CsA, FK-506 and pimecrolimus, and suggest that calcineurin may have a role in the regulation of iNOS expression.
More Related Videos
09:01Extraction and Quantification of Soluble, Radiolabeled Inositol Polyphosphates from Different Plant Species using SAX-HPLC
Published on: June 26, 2020
09:22Absolute Quantitation of Inositol Pyrophosphates by Capillary Electrophoresis Electrospray Ionization Mass Spectrometry
Published on: August 13, 2021
Related Concept Videos
Eukaryotic Transcription Inhibitors
Eukaryotic transcription inhibitors usually contain two distinct domains, a DNA...
Inhibitors of Viral Protein Synthesis
Regulation of the Unfolded Protein Response
Phosphoinositides and PIPs
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Experimental RNAi
RNA Interference
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...
