title: 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 and infiltrating cells are critical to inflammation in renal ischemia-reperfusion injury. IL-37, a newly described IL-1 family member, inhibits IL-18-dependent pro-inflammatory cytokine production by its binding to IL-18 receptors and IL-18 binding protein. The potential role of IL-37 in renal ischemia-reperfusion injury is unknown. Here we found that exposure of tubular epithelial cells to exogenous IL-37 downregulated hypoxia and the IL-18-induced expression of TNFα, IL-6, and IL-1β. Importantly, human PT-2 tubular epithelial cells have inducible expression of IL-37. Moreover, pro-inflammatory cytokine expression was augmented in IL-37 mRNA-silenced tubular epithelial cells and inhibited by transfection with pCMV6-XL5-IL-37. In a mouse ischemic injury model, transgenic expression of human IL-37 inhibited kidney expression of TNFα, IL-6, and IL-1β and improved mononuclear cell infiltration, kidney injury, and function. Thus, human tubular epithelial cells express the IL-18 contra-regulatory protein IL-37 as 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 ischemic injury and transplantation.
authors.affiliation: Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada.
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 1] Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada [2] Department of Pathology, London Health Sciences, Western University, London, Ontario, Canada [3] Department of Medicine, London Health Sciences, Western University, London, Ontario, Canada.
authors.forename: Zhu-Xu
authors.initials: ZX
authors.lastname: Zhang
authors.affiliation: Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada.
authors.forename: Dameng
authors.initials: D
authors.lastname: Lian
authors.affiliation: Department of Pathology, London Health Sciences, Western University, London, Ontario, Canada.
authors.forename: Aaron
authors.initials: A
authors.lastname: Haig
authors.affiliation: Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada.
authors.forename: Rabindra N
authors.initials: RN
authors.lastname: Bhattacharjee
authors.affiliation: 1] Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, London, Ontario, Canada [2] Department of Medicine, London Health Sciences, Western University, London, Ontario, Canada.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Jevnikar
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000276:immunology* / Q000293:injuries*; D007684:Kidney Tubules / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D053724:Receptors, Interleukin-18 / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: D016207:Cytokines; C508587:IL37 protein, human; D018836:Inflammation Mediators; D007375:Interleukin-1; D020382:Interleukin-18; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053724:Receptors, Interleukin-18