Geranylgeranyl pyrophosphate amplifies Treg differentiation via increased IL‐2 expression to ameliorate DSS‐induced colitis

Blocking the mevalonate pathway for cholesterol reduction by using statin may have adverse effects including statin‐induced colitis. Moreover, one of the predisposing factors for colitis is an imbalanced CD4+ T cell, which can be observed on the complete deletion of HMG‐CoA reductase (HMGCR), a target of statins. In this study, we inquired geranylgeranyl pyrophosphate (GGPP) is responsible for maintaining the T‐cell homeostasis. Following dextran sulfate sodium (DSS)‐induced colitis, simvastatin increased the severity of disease, while cotreatment with GGPP, but not with cholesterol, reversed the disease magnitude. GGPP ameliorated DSS‐induced colitis by increasing Treg cells. GGPP amplified Treg differentiation through increased IL‐2/STAT 5 signaling. GGPP prenylated Ras protein, a prerequisite for extracellular signal‐regulated kinase (ERK) pathway activation, leading to increased IL‐2 production. Higher simvastatin dose increased the severity of colitis. GGPP ameliorated simvastatin‐increased colitis by increasing Treg cells. Treg cells, which have the capacity to suppress inflammatory T cells and were generated through IL‐2/STAT5 signaling, increased IL‐2 production through prenylation and activation of the Ras/ERK pathway. Geranylgeranyl pyrophosphate (GGPP) prenylates Ras protein and induces IL‐2 production via Ras/ERK pathway in CD4 T cell. The increased IL‐2 enhances STAT5 activity to increase Foxp3 Treg differentiation. Thus, GGPP treatment ameliorates DSS‐induced colitis via increasing Treg cells.