Role for IKK2- and NEMO-Kinase Mediated Nuclear Factor kappa B (NF-κB) Activation in CD4+ T Lymphocytes in Nephrotoxic Serum Nephritis (NTN) Induced Glomerulonephritis Mice
Universität Hamburg, Medizin. Medizin, 2016
Online
Hochschulschrift
Accumulative evidences indicated the critical role for CD4+ T cells in the pathogenesis of glomerulonephritis, the molecule(s) involving in regulation of the development and functions of CD4+ T cells to mediate glomerulonephritis is poorly understood. NF-κB transcription family is known as a major regulator of T cells development and functions and participates into multiple inflammation based diseases. However, whether NF-κB functions in CD4+ T cells are critical for glomerulonephritis or not remains unclear. NF-κB is activated by an IκB kinase (IKK) complex comprised of two distinct kinase subunits, IKK1 (IKKα) and IKK2 (IKKβ), plus a regulatory protein, NEMO (IKKγ), which is essential for activation of NF-κB. Here, we specifically deleted IKK2 and/or NEMO in CD4+ T cells to investigate the role of canonical NF-κB pathway in glomerulonephritis. In general, our data showed that knockout of IKK2 and/or NEMO in CD4+ T cells decreased the number of T cells as previously reported under physiological conditions. However, mice with knockout of IKK2 and/or NEMO in CD4+ T cells did not alter the progression of glomerulonephritis showing similar renal functions by examination of albumin-to-creatinine ratio and blood urea nitrogen levels (BUN), and comparable morphology of kidney by quantifying the glomerular/tubulointerstitium damage, and renal crescent levels compared to control mice at 10th day in a well-established nephrotoxic serum nephritis (NTN) induced glomerulonephritis model. We did find an increased infiltration ability of CD3+ and CD4+ T cells into kidney after NTN induction in all types of knockout mice but eventually exhibited similar number of CD3+ T cells and comparable percentage of CD4+ T cells residual in overall renal and glomerular tissues by immunohistochemical and FACS analysis. Interestingly, the infiltration levels for different subtypes of CD4+ T cells were distinct from each other in the injury kidney: more Th1 and Th17 cells and less Treg cells were observed in IKK2 and/or NEMO knockout mice comparing with control mice after NTN induction. However, similar expression levels of proinflammatoy chemokines, including IL-1b, TNF-α, CCL2, CCL5 and CCL20 in all types of knockout mice and control mice, were detected. Consistently, the activation of inflammatory related regulator NF-κB in renal cells was also unaltered by western blotting analysis. Thus, our observations implied that inactivation of NF-κB in CD4+ T cells is not involved in alteration of the severity of NTN induced glomerulonephritis. In addition, to uncover which molecules in CD4+ T cells participate into NTN induced glomerulonephritis, microarray based genome profiling was performed by comparing genes expression in CD4+ T cells from kidney spleen that with or without NTN induction. Thus, to identify novel molecule(s) which are essential/critical for T cells mediated glomerulonephritis greatly benefits to clinic treatment of inflammatory renal diseases.
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Role for IKK2- and NEMO-Kinase Mediated Nuclear Factor kappa B (NF-κB) Activation in CD4+ T Lymphocytes in Nephrotoxic Serum Nephritis (NTN) Induced Glomerulonephritis Mice
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Autor/in / Beteiligte Person: | Chen, Meilan |
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Veröffentlichung: | Universität Hamburg, Medizin. Medizin, 2016 |
Medientyp: | Hochschulschrift |
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