T-lymphocyte-specific knockout of IKK-2 or NEMO induces Th17 cells in an experimental nephrotoxic nephritis mouse model.
Experimental nephrotoxic serum nephritis (NTN) is a model for T-cell-mediated human rapid progressive glomerulonephritis. T-cell receptor stimulation involves intracellular signaling events that ultimately lead to the activation of transcription factors, such as NF-κB. We explored the involvement of the NF-κB components IKK-2 and NEMO in NTN, by using cell-specific knockouts of IKK-2 and NEMO in CD4+ T lymphocytes. Our results demonstrate that although the course of disease was not grossly altered in CD4xIKK2Δ and CD4xNEMOΔ animals, renal regulatory T cells were significantly reduced and T helper (Th)1 and Th17 cells significantly increased in both knockout mouse groups. The expression of the renal cytokines and chemokines IL-1β, CCL-2, and CCL-20 was also significantly altered in both knockout mice. Lymphocyte transcriptome analysis confirmed the increased expression of Th17-related cytokines in spleen CD4+ T cells. Moreover, our array data demonstrate an interrupted canonical NF-κB pathway and an increased expression of noncanonical NF-κB pathway-related genes in nephritic CD4xNEMOΔ mice, highlighting different downstream effects of deletion of IKK-2 or NEMO in T lymphocytes. We propose that better understanding of the role of IKK-2 and NEMO in nephritis is essential for the clinical application of kinase inhibitors in patients with glomerulonephritis.-Guo, L., Huang, J., Chen, M., Piotrowski, E., Song, N., Zahner, G., Paust, H.-J., Alawi, M., Geffers, R., Thaiss, F. T-lymphocyte-specific knockout of IKK-2 or NEMO induces Th17 cells in an experimental nephrotoxic nephritis mouse model.
['Guo|Linlin|L|', 'Huang|Jiabin|J|', 'Chen|Meilan|M|', 'Piotrowski|Eveline|E|', 'Song|Ning|N|', 'Zahner|Gunther|G|', 'Paust|Hans-Joachim|HJ|', 'Alawi|Malik|M|', 'Geffers|Robert|R|', 'Thaiss|Friedrich|F|']
D000818:Animals D002478:Cells, Cultured D016207:Cytokines D004195:Disease Models, Animal D051550:I-kappa B Kinase D047908:Intracellular Signaling Peptides and Proteins D008297:Male D051379:Mice D018345:Mice, Knockout D016328:NF-kappa B D009393:Nephritis D010766:Phosphorylation D015398:Signal Transduction D013601:T-Lymphocytes D058504:Th17 Cells
NTN transcription factors NF-κB transcriptome canonical/noncanonical pathway