title: IL-18 neutralization ameliorates obstruction-induced epithelial-mesenchymal transition and renal fibrosis.
abstract: Ureteral obstruction results in renal fibrosis in part due to inflammatory injury. The role of interleukin-18 (IL-18), an important mediator of inflammation, in the genesis of renal fibrosis was studied using transgenic mice overexpressing human IL-18-binding protein. In addition, HK-2 cells were analyzed following direct exposure to IL-18 compared to control media. Two weeks after ureteral obstruction, the kidneys of wild-type mice had a significant increase in IL-18 production, collagen deposition, alpha-smooth muscle actin and RhoA expression, fibroblast and macrophage accumulation, chemokine expression, and transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor-alpha (TNF-alpha) production, whereas E-cadherin expression was simultaneously decreased. The transgenic mice with neutralized IL-18 activity exhibited significant reductions in these indicators of obstruction-induced renal fibrosis and epithelial- mesenchymal transition, without demonstrating alterations in TGF-beta1 or TNF-alpha activity. Similarly, the HK-2 cells exhibited increased alpha-smooth muscle actin expression and collagen production, and decreased E-cadherin expression in response to IL-18 stimulation without alterations in TNF-alpha or TGF-beta1 activity. Our study demonstrates that IL-18 is a significant mediator of obstruction-induced renal fibrosis and epithelial- mesenchymal transition independent of downstream TGF-beta1 or TNF-alpha production.
authors.affiliation: Department of Urology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Ahmad H
authors.initials: AH
authors.lastname: Bani-Hani
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Leslie
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Campbell
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Meldrum
authors.forename: Honji
authors.initials: H
authors.lastname: Zhang
authors.forename: Karen
authors.initials: K
authors.lastname: Hile
authors.forename: Kirstan K
authors.initials: KK
authors.lastname: Meldrum
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000235:genetics; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology*; D005355:Fibrosis; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D020382:Interleukin-18 / Q000502:physiology*; D007668:Kidney / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D008297:Male; D008648:Mesoderm / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000199:Actins; D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C544013:alpha-smooth muscle actin, mouse; C118370:interleukin-18 binding protein; D003094:Collagen