Universität zu Köln

Gotot, Janine, Piotrowski, Eveline, Otte, Martin S., Tittel, Andre P., Yao, Chen, Ziegelbauer, Karl, Panzer, Ulf, Garbi, Natalio, Kurts, Christian and Thaiss, Friedrich (2016). Inhibitor of NF kappa B Kinase Subunit 2 Blockade Hinders the Initiation but Aggravates the Progression of Crescentic GN. J. Am. Soc. Nephrol., 27 (7). S. 1917 - 1925. WASHINGTON: AMER SOC NEPHROLOGY. ISSN 1533-3450

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Abstract

The NF kappa B 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 NF kappa B inhibitors are promising anti-inflammatory drug candidates. Here, we investigated whether inhibiting the NF kappa B-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Gotot, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Piotrowski, Eveline UNSPECIFIED UNSPECIFIED UNSPECIFIED Otte, Martin S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tittel, Andre P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yao, Chen UNSPECIFIED UNSPECIFIED UNSPECIFIED Ziegelbauer, Karl UNSPECIFIED UNSPECIFIED UNSPECIFIED Panzer, Ulf UNSPECIFIED UNSPECIFIED UNSPECIFIED Garbi, Natalio UNSPECIFIED UNSPECIFIED UNSPECIFIED Kurts, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Thaiss, Friedrich UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-271137
DOI:	10.1681/ASN.2015060699
Journal or Publication Title:	J. Am. Soc. Nephrol.
Volume:	27
Number:	7
Page Range:	S. 1917 - 1925
Date:	2016
Publisher:	AMER SOC NEPHROLOGY
Place of Publication:	WASHINGTON
ISSN:	1533-3450
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language REGULATORY T-CELLS; DENDRITIC CELLS; IMMUNE-RESPONSE; IKK-BETA; KIDNEY; GLOMERULONEPHRITIS; INFLAMMATION; EXPRESSION; DEPENDENCE; PREVENTS Multiple languages Urology & Nephrology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27113