Interleukin-17 Cytokines Are Critical in Development of Fatal Lupus Glomerulonephritis

被引:155
作者
Pisitkun, Prapaporn [1 ]
Ha, Hye-Lin [1 ]
Wang, Hongshan [1 ]
Claudio, Estefania [1 ]
Tivy, Caitlyn C. [1 ]
Zhou, Hua [2 ]
Mayadas, Tanya N. [3 ]
Illei, Gabor G. [2 ]
Siebenlist, Ulrich [1 ]
机构
[1] NIAID, Immune Activat Sect, Immunoregulat Lab, Bethesda, MD 20892 USA
[2] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA
[3] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Excellence Vasc Biol,Dept Pathol, Boston, MA 02115 USA
关键词
FC-GAMMA-RIIB; COLLAGEN-INDUCED ARTHRITIS; ADAPTER PROTEIN CIKS/ACT1; AUTOIMMUNE-DISEASE; INTERFERON-GAMMA; CLASS SWITCH; MOUSE MODEL; B-CELLS; RECEPTOR; EXPRESSION;
D O I
10.1016/j.immuni.2012.08.014
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Systemic lupus erythematosus is a potentially fatal autoimmune disease. Although interleukin-17 (IL-17) has been linked to human lupus and mouse models of this disease, it has not been addressed whether this cytokine plays a critical role in fatal lupus pathology. Here we have demonstrated that increased production of IL-17 cytokines and their signaling via the adaptor protein CIKS (a.k.a. Traf3ip2, Act1) critically contributed to lethal pathology in an FcgammaR2b-deficient mouse model of lupus. Mice lacking IL-17 and especially those lacking CIKS showed greatly improved survival and were largely protected from development of glomerulonephritis. Importantly in this model, potential effects of IL-17 cytokines on antibody production could be distinguished from critical local contributions in kidneys, including recruitment of neutrophils and monocytes. These findings provide the proof of principle that signaling by IL-17 family cytokines mediated via CIKS presents promising therapeutic targets for the treatment of systemic lupus erythematosus, especially in cases with kidney involvement.
引用
收藏
页码:1104 / 1115
页数:12
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