Isoprenoid Depletion Increases Cytokine mRNA Levels in Primary Human Monocytes

Abstract

Mevalonate Kinase Deficiency (MKD) is an autoinflammatory disease caused by mutations in the mevalonate kinase (MVK) gene, which produces an enzyme responsible for the production of isoprenoids. Previous research in various model systems has demonstrated that depletion of isoprenoids leads to inflammasome activation and increased levels of secreted IL‐1B on a post‐translational level. However, patient data indicates that MKD is a multi‐cytokine disease with increased plasma levels of cytokines such as TNF‐alpha, IL‐6, and IFN‐gamma. In order to study the mechansims responsible for these changes, the mevalonate pathway was inhibited with lovastatin in peripheral blood mononulcear cells (PBMCs) and monocytes isolated from the blood of healthy donors followed by stimulation with lipopolysaccharide (LPS) to induce an inflammatory response. Lovastatin treatment resulted in significantly increased levels of TNF‐alpha, IL‐6, IL‐12p40, and IFN‐gamma mRNA in both PBMCs and monocytes following LPS stimulation as compared to control cells. Lovastatin treatment did not alter IL‐1B, CD14, or IL‐18 mRNA levels either before or after LPS stimulation. Addition of mevalonate to the cells treated with lovastatin prevented the increased cytokine mRNA levels indicating that these changes are due to inhibition of the mevalonate pathway. These results indicate that isoprenoid depletion alters the expression of multiple cytokines on the mRNA level in primary human monocytes, which can be used as a model system ex vivo to study these changes.Support or Funding InformationDickinson College Faculty Start‐up and Research & Development Committee FundingThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.