IL-37 Inhibits IL-18-Induced Tubular Epithelial Cell Expression of Pro-Inflammatory Cytokines and Renal Ischemia-Reperfusion Injury.

Abstract

Cytokines and chemokines produced by tubular epithelial cells as well as infiltrating cells are critical to inflammation in renal ischemia-reperfusion injury. IL-37 is a newly described IL-1 family member, which inhibits IL-18 dependent pro-inflammatory cytokine production through its binding to IL-18 receptors and IL-18 binding protein. The potential role of IL-37 in renal ischemia injury is unknown. In this study renal tubular epithelial cells were shown to basally express IL-18 receptors and IL-18 binding protein. Importantly, human PT-2 tubular epithelial cells have inducible expression of IL-37. Exposure of tubular epithelial cells to exogenous IL-37 (300ng/mL) down-regulated IL-18 induced expression of TNFα, IL-6 and IL-1β. Moreover, pro-inflammatory cytokine expression was augmented in IL-37mRNA silenced tubular epithelial cells and inhibited by transfection with pCMV6-XL5-IL37. In a mouse ischemia injury model, transgenic expression of human IL-37 inhibited kidney expression of TNFα, IFNγ, IL-6 and IL-1β, and improved histological infiltration, injury and kidney function. This report demonstrates human tubular epithelial cells express the IL-18 contra-regulatory protein IL-37 and suggests IL-37 production by tubular epithelial cells is an endogenous control mechanism to reduce inflammation. Augmenting kidney IL-37 may represent a novel strategy to suppress renal injury responses, and promote kidney function after renal ischemia injury and transplantation.