Monocyte Production of IFN-γ Is Interleukin-12 Dependent in a Model of Mevalonate Kinase Deficiency

Mevalonate Kinase Deficiency (MKD) is an autoinflammatory disease caused by mutations in the mevalonate kinase gene, which produces an enzyme responsible for the production of isoprenoids in the mevalonate pathway. Patient data indicate that MKD is a multicytokine disease with increased plasma levels of cytokines such as tumor necrosis factor-α, interleukin (IL)-6, and interferon (IFN)-γ. To study the mechanisms responsible for these changes, the mevalonate pathway was inhibited with lovastatin in peripheral blood mononuclear 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 increased levels of IL-6, IL-12p40, and IFN-γ mRNA in both PBMCs and monocytes following LPS stimulation compared with control cells. An IL-12 neutralizing antibody blocked the increased levels of IFN-γ mRNA following lovastatin treatment in PBMCs indicating that this effect is dependent on IL-12. Flow cytometry experiments indicated that monocytes, not lymphocytes or granulocytes, are the source of increased IFN-γ and that both classical and nonclassical/intermediate monocytes express IFN-γ. These results indicate that blocking IL-12 or IFN- γ may be therapeutic options for MKD patients.