IL-18 neutralization ameliorates obstruction-induced epithelial-mesenchymal transition and renal fibrosis

被引：86

作者：

Bani-Hani, Ahmad H. ^{[1
]}

Leslie, Jeffery A. ^{[1
]}

Asanuma, Hiroshi ^{[1
]}

Dinarello, Charles A. ^{[2
]}

Campbell, Matthew T. ^{[1
]}

Meldrum, Daniel R. ^{[3
]}

Zhang, Honji ^{[1
]}

Hile, Karen ^{[1
]}

Meldrum, Kirstan K. ^{[1
]}

机构：

[1] Indiana Univ Sch Med, Dept Urol, Indianapolis, IN USA

[2] Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA

[3] Indiana Univ Sch Med, Dept Surg, Indianapolis, IN USA

来源：

KIDNEY INTERNATIONAL | 2009年 / 76卷 / 05期

关键词：

EMT; IL-18; TGF-beta; 1; TNF-alpha; tubulointerstitial fibrosis; GROWTH-FACTOR-BETA; UNILATERAL URETERAL OBSTRUCTION; ACUTE TUBULAR-NECROSIS; TUBULOINTERSTITIAL FIBROSIS; INTERSTITIAL FIBROSIS; UP-REGULATION; MYOFIBROBLAST TRANSDIFFERENTIATION; TISSUE FIBROSIS; GENE-EXPRESSION; ANGIOTENSIN-II;

D O I：

10.1038/ki.2009.216

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

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-beta 1 (TGF-beta 1) 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-beta 1 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-beta 1 activity. Our study demonstrates that IL- 18 is a significant mediator of obstruction-induced renal fibrosis and epithelial-mesenchymal transition independent of downstream TGF-beta 1 or TNF-alpha production.

引用

页码：500 / 511

页数：12

共 58 条

[31] Activation of the Erk pathway is required for TGF-β1-induced EMT in vitro [J].

Lu, X ;

Law, BK ;

Chytil, AM ;

Brown, KA ;

Aakre, ME ;

Moses, HL .

NEOPLASIA, 2004, 6 (05) :603-610

[32] Central role for Rho in TGF-β1-induced α-smooth muscle actin expression during epithelial-mesenchymal transition [J].

Masszi, A ;

Di Ciano, C ;

Sirokmány, G ;

Arthur, WT ;

Rotstein, OD ;

Wang, JX ;

McCulloch, CAG ;

Rosivall, L ;

Mucsi, I ;

Kapus, A .

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2003, 284 (05) :F911-F924

[33] TNF-α neutralization ameliorates obstruction-induced renal fibrosis and dysfunction [J].

Meldrum, K. K. ;

Misseri, R. ;

Metcalfe, P. ;

Dinarello, C. A. ;

Hile, K. L. ;

Meldrum, D. R. .

AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 2007, 292 (04) :R1456-R1464

[34] Neutrophil-independent mechanisms of caspase-1-and IL-18-mediated ischemic acute tubular necrosis in mice [J].

Melnikov, VY ;

Faubel, S ;

Siegmund, B ;

Lucia, MS ;

Ljubanovic, D ;

Edelstein, CL .

JOURNAL OF CLINICAL INVESTIGATION, 2002, 110 (08) :1083-1091

[35] Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure [J].

Melnikov, VY ;

Ecder, T ;

Fantuzzi, G ;

Siegmund, B ;

Lucia, MS ;

Dinarello, CA ;

Schrier, RW ;

Edelstein, CL .

JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (09) :1145-1152

[36] Inflammatory mediators and growth factors in obstructive renal injury [J].

Misseri, R ;

Rink, RC ;

Meldrum, DR ;

Meldrum, KK .

JOURNAL OF SURGICAL RESEARCH, 2004, 119 (02) :149-159

[37] Antibody to transforming growth factor-β ameliorates tubular apoptosis in unilateral ureteral obstruction [J].

Miyajima, A ;

Chen, J ;

Lawrence, C ;

Ledbetter, S ;

Soslow, RA ;

Stern, J ;

Jha, S ;

Pigato, J ;

Lemer, ML ;

Poppas, DP ;

Vaughan, ED ;

Felsen, D .

KIDNEY INTERNATIONAL, 2000, 58 (06) :2301-2313

[38] Neutralization of IL-18 reduces neutrophil tissue accumulation and protects mice against lethal Escherichia coli and Salmonella typhimurium endotoxemia [J].

Netea, MG ;

Fantuzzi, G ;

Kullberg, BJ ;

Stuyt, RJL ;

Pulido, EJ ;

McIntyre, RC ;

Joosten, LAB ;

Van der Meer, JWM ;

Dinarello, CA .

JOURNAL OF IMMUNOLOGY, 2000, 164 (05) :2644-2649

[39] Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats [J].

Ng, YY ;

Huang, TP ;

Yang, WC ;

Chen, ZP ;

Yang, AH ;

Mu, W ;

Nikolic-Paterson, DJ ;

Atkins, RC ;

Lan, HY .

KIDNEY INTERNATIONAL, 1998, 54 (03) :864-876

[40]

Olee T, 1999, J IMMUNOL, V162, P1096

← 1 2 3 4 5 6 →