Inhibitor of NFκB Kinase Subunit 2 Blockade Hinders the Initiation but Aggravates the Progression of Crescentic GN
| Autor: | Guo Linlin, Eveline Piotrowski, Ulf Panzer, Friedrich Thaiss, Martin Sylvester Otte, Christian Kurts, Chen Yao, Natalio Garbi, André P. Tittel, Janine Gotot, Karl Ziegelbauer |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male Pyridines medicine.medical_treatment Protein Serine-Threonine Kinases Severity of Illness Index 03 medical and health sciences Mice Immune system Glomerulonephritis Oxazines medicine Animals Transcription factor Kidney Kinase business.industry Immunosuppression General Medicine Acquired immune system medicine.disease 030104 developmental biology medicine.anatomical_structure Nephrology Immunology Disease Progression Cell activation business Brief Communications |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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