Inhibitor of NFκB Kinase Subunit 2 Blockade Hinders the Initiation but Aggravates the Progression of Crescentic GN.

Autor:	Gotot J; Institute of Experimental Immunology, Rheinische Friedrich Wilhelms University, Bonn, Germany;, Piotrowski E; Third Medical Department of Clinical Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany;, Otte MS; Institute of Experimental Immunology, Rheinische Friedrich Wilhelms University, Bonn, Germany; Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne Germany; and., Tittel AP; Institute of Experimental Immunology, Rheinische Friedrich Wilhelms University, Bonn, Germany;, Linlin G; Third Medical Department of Clinical Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany;, Yao C; Third Medical Department of Clinical Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany;, Ziegelbauer K; Global Drug Discovery, TRG Oncology/GT, Bayer Pharma AG, Berlin, Germany., Panzer U; Third Medical Department of Clinical Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany;, Garbi N; Institute of Experimental Immunology, Rheinische Friedrich Wilhelms University, Bonn, Germany;, Kurts C; Institute of Experimental Immunology, Rheinische Friedrich Wilhelms University, Bonn, Germany; ckurts@web.de thaiss@uke.de., Thaiss F; Third Medical Department of Clinical Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany; ckurts@web.de thaiss@uke.de.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2016 Jul; Vol. 27 (7), pp. 1917-24. Date of Electronic Publication: 2015 Nov 16.
DOI:	10.1681/ASN.2015060699
Abstrakt:	The NFκB transcription factor family facilitates the activation of dendritic cells (DCs) and CD4(+) T helper (Th) cells, which are important for protective adaptive immunity. Inappropriate activation of these immune cells may cause inflammatory disease, and NFκB inhibitors are promising anti-inflammatory drug candidates. Here, we investigated whether inhibiting the NFκB-inducing kinase IKK2 can attenuate crescentic GN, a severe DC- and Th cell-dependent kidney inflammatory disease. Prophylactic pharmacologic IKK2 inhibition reduced DC and Th cell activation and ameliorated nephrotoxic serum-induced GN in mice. However, therapeutic IKK2 inhibition during ongoing disease aggravated the nephritogenic immune response and disease symptoms. This effect resulted from the renal loss of regulatory T cells, which have been shown to protect against crescentic GN and which require IKK2. In conclusion, although IKK2 inhibition can suppress the induction of nephritogenic immune responses in vivo, it may aggravate such responses in clinically relevant situations, because it also impairs regulatory T cells and thereby, unleashes preexisting nephritogenic responses. Our findings argue against using IKK2 inhibitors in chronic GN and perhaps, other immune-mediated diseases. (Copyright © 2016 by the American Society of Nephrology.)
Databáze:	MEDLINE
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