title: Inhibitor of NFκB Kinase Subunit 2 Blockade Hinders the Initiation but Aggravates the Progression of Crescentic GN.
abstract: 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.
authors.affiliation: Institute of Experimental Immunology, Rheinische Friedrich Wilhelms University, Bonn, Germany;
authors.forename: Janine
authors.initials: J
authors.lastname: Gotot
authors.affiliation: Third Medical Department of Clinical Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany;
authors.forename: Eveline
authors.initials: E
authors.lastname: Piotrowski
authors.affiliation: Institute of Experimental Immunology, Rheinische Friedrich Wilhelms University, Bonn, Germany; Department of Otorhinolaryngology, Head and Neck Surgery, University of Cologne Germany; and.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Otte
authors.affiliation: Institute of Experimental Immunology, Rheinische Friedrich Wilhelms University, Bonn, Germany;
authors.forename: André P
authors.initials: AP
authors.lastname: Tittel
authors.affiliation: Third Medical Department of Clinical Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany;
authors.forename: Guo
authors.initials: G
authors.lastname: Linlin
authors.affiliation: Third Medical Department of Clinical Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany;
authors.forename: Chen
authors.initials: C
authors.lastname: Yao
authors.affiliation: Global Drug Discovery, TRG Oncology/GT, Bayer Pharma AG, Berlin, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Ziegelbauer
authors.affiliation: Third Medical Department of Clinical Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany;
authors.forename: Ulf
authors.initials: U
authors.lastname: Panzer
authors.affiliation: Institute of Experimental Immunology, Rheinische Friedrich Wilhelms University, Bonn, Germany;
authors.forename: Natalio
authors.initials: N
authors.lastname: Garbi
authors.affiliation: Institute of Experimental Immunology, Rheinische Friedrich Wilhelms University, Bonn, Germany; ckurts@web.de thaiss@uke.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.affiliation: Third Medical Department of Clinical Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany; ckurts@web.de thaiss@uke.de.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Thaiss
mesh_terms: D000818:Animals; D018450:Disease Progression; D005921:Glomerulonephritis / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D010078:Oxazines / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D012720:Severity of Illness Index; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D010078:Oxazines; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D000097782:NF-kappaB-Inducing Kinase; C502972:7-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido(2,3-d)(1,3)oxazin-2-one
keywords: chronic kidney disease; glomerulonephritis; immunology; immunosuppression; lymphocytes; progression of chronic renal failure