might play on activation of NF-κB and functional parameters in NTN mice.
We first characterized the effect of the NTN model on renal function, proteinuria, expression of chemokines, and monocytes and T-cells infiltration.
During the 21 days observation period after induction of NTN, BUN and albuminuria significantly increased, the expression of chemokines were markedly upregulated, and T cells and monocyte/dendritic cells renal infiltration was significant in NTN mice when compared with non-nephritis control mice.
By morphology, we could demonstrate severe renal damage after disease induction. The glomerular changes included hypercellularity, formation of cellular crescents, and intraglomerular deposition of PAS-positive material. The tubulointerstitial compartment showed protein casts, tubular dilation, necrosis and atrophy. The results suggest that the nephrotoxic serum nephritis model induced by a sheep-anti-mouse GBM antiserum is an effective glomerulonephritis model which resembles human rapid progressive glomerulonephritis.
The functional parameters examined demonstrate a dynamic behavior with an increase within the induction period of the NTN disease during the first 4 to 7 days and a decline thereafter with an incomplete resolution, however, within the 21 days observation period.
To search for possible relevant mechanisms to explain this dynamic process we examined the activation of the transcription factor NF-κB. Gel shift experiments demonstrated an oscillation of NF-kappa B activation with a first
peak during the induction phase at days 2 to 4 and additional peaks at days 10 and 21 after NTN induction.
These are the first in vivo data demonstrating NF-κB oscillation after the induction of an inflammatory renal disease in mice. In the Thy-1.1 nephritis model in rats and the LPS-nephritis model in mice we have recently demonstrated a biphasic NF-κB activation51. In these models we could demonstrate that the activation of NF-κB during the early period plays a role in the induction of the disease, during the later period of the disease, however, NF-κB activation plays a pivotal role in the resolution process of the nephritis54
55. The idea of NF-κB oscillatory dynamics having a key functional role in stress-response systems has been described recently at the single cellular level.
NF-κB is one of the major families of transcription factors activated during the inflammatory response in renal inflammatory diseases. Inhibitory factor-κB kinase 2 (IKK-2) has been shown to play a pivotal role in cytokine-induced NF-κB activation in glomerular mesangial or tubular epithelial cells and also in disease-relevant infiltrating inflammatory cells. Nevertheless, the potential effect of specific IKK-2 inhibitor has not been described in detail in glomerular inflammatory diseases. Based on the own results of the above described NF-κB oscillation during inflammatory renal disease, the effects of NF-κB blockade are probably highly dependent on the time course of the disease56 51,57. Therefore, blocking of NF-κB at different phases of renal inflammation might have profound effects on the outcome of the disease. Next, intervention with a specific IKK2-inhibitor to block NF-κB activation via the classical pathway was performed to establish NF-κB as a possible new target for the treatment of renal
inflammatory disease.
NF-κB is an important regulator of inflammation of immune responses by mediating proinflammatory gene expression. Under basal conditions NF-κB dimers remain in the cytoplasm as an inactive form. A family of inhibitory proteins, IκBs, bind NF-κB and mask nuclear localization signal, thereby blocking nuclear translocation. Exposure of cells to a varity of proinflammatory stimuli leads to the rapid phosphorylation, ubiquitinylation, and ultimately proteolytic degradation of IκB by IκB kinase (IKKα and IKKβ), which allows nuclear translocation of NF-κB and subsequent gene transcripton22. In the two IKK subunits, IKKα and IKKβ, IKKβ is most important for rapid degradation of NF-κB–bound IκBs32 33.The affinity of Compound A for IKKβ over IKKα is greater than 50-fold despite the 50% sequence homology between the two IKK subunits. As such, it has a significant advantage over other NF-κB inhibitors in its specific suppression of one kinase critical to the classical activation of the NF-κB pathway. IKKβ plays a pivotal role in the nuclear factor-κB-regulated production of proinflammatory molecules by stimuli such as TNFα and IL-1β.
Multiple studies have demonstrated that IKKβ inhibition could reduce proinflammatory mediators and prevent antigen-induced T cell proliferation in vitro and vivo43 58.We therefore applied the IKKβ inhibitor CpdA to block the classical pathway of NF-κB activation at the initiation and later phase of nephritis in the NTN model and get further insight into the functional role of IKKβ.
Our experiments focused on the first 10 days after NTN induction. During this period we have demonstrated two peaks of NF-κB activation, one at day 4
and the second at day 10. The NTN mice were treated with CpdA, a specific IKK2-inhibitor, at different time intervals after the induction of the disease.
Nuclear translocation of NF-κB was complete suppressed by CpdA in animals pretreated with CpdA starting before disease induction at day -1 until day 10 when compared with non-treated NTN mice. The signal of NF-κB DNA-binding was also significantly reduced at day 10 in mice pretreated with CpdA before NTN induction until 4 days, however, was not significantly reduced in animals in which CpdA treatment was delayed until day 4 when compared with non-treated nephritic mice.
To determine the possible therapeutic role of IKKβ inhibition with CpdA in NTN glomerulonephritis renal function was examined in the different CpdA treated groups of NTN mice. BUN significantly decreased in the mice pretreated until 10 days. But there was no significant change in the mice with the interrupted and delayed treatment protocols when compared with non-treated nephritis mice. Albuminuria was also significantly reduced in the pretreated group not, however, in the other treatment groups versus non-treated NTN mice.
To assess histological changes, PAS staining of kidneys from CpdA treated NTN mice and non-treated NTN mice was examined in detail. The glomerular damage score showed no significant differences between nephritic animals with interrupted and delayed CpdA treatment protocols when compared with non-treated NTN mice. However, kidney morphology of mice pretreated with CpdA and continued treatment until 10 days after NTN-induction was almost completely normal. These data demonstrated that the IKKβ inhibitor CpdA when applicated during the whole observation period of NTN-glomerulonephritis could almost completely abolish NTN induction in mice and preserve kidney
function.
To further address the pathophysiological role of IKKβ-inhibition infiltration of tubulointersitial CD3+ T cells, F4/80+ monocytes/dendritic cells and glomerular MAC-2+ monocytes/macrophages was examined. Inflammatory cell infiltration was significantly reduced in pretreated animals not, however, in animals in which CpdA-treatment was interrupted or delayed.
Correlating, quantitative PCR analyses demonstrated reduced chemokine expression of MCP-1/CCL2, RANTES/CCL5 (both attract mostly neutrophils and monocytes) and CXCL10/IP-10 (attracts T cells) in the group pretreated with CpdA until 10 days. There was no significant change between CpdA pretreated until 4 days mice, CpdA posttreated mice and CpdA non-treated NTN mice. The expression of TNFα and IL-1β was, however, significantly downregulated in all of the CpdA treated groups when compared with CpdA non-treated NTN mice.
In the regulation of TNFα and IL-1β cytokines NF-κB activation via the canonical pathway is the master transcription factor which regulates their expression. Therefore these data demonstrate that the activation of NF-κB has been effectively blocked in all CpdA treated groups.
These differences in the expression profiles described may be due to differential regulation of expression of NF-κB induced genes by the IKKß -inhibitor. Cell specific differences in the activation of IKKß and NF-κB have been recognized recently. It has been demonstrated that IKKß plays a tissue-specific role in inflammation. In resident tissue cells, IKKß-mediated NF- κB activation drives cytokine and chemokine production required to initiate the
inflammatory response. However, NF-κB activation in resident macrophages or leukocytes recruited during inflammation has an antiinflamatory role5960.
In conclusion, our experiments demonstrate an oscillation of NF-κB activation during a 21 days observation period in the NTN model, with a first peak during the induction phase at days 2 and 4 and further peaks at days 10 and 21 after the induction of the disease. IKKβ inhibition significantly down regulated renal inflammatory cells infiltration and chemokine expression at day 10 when treatment was started before induction of the disease not, however, when treatment was interrupted or delayed. The selective IKKβ inhibitor reduced NF-κB DNA-binding activity at day 10 in pretreated animals and also in animals in which treatment was interrupted not, however, in the group in which treatment was delayed. These results demonstrate that NF-κB is a master transcriptional regulator in experimental glomerulonephritis. However, other transcription factors might become major players during the later course of the disease. An interaction between the protein kinases JNK1 and IKK2 or the IKK/NF-κB and STAT3 pathways have been described recently to serve as critical molecular links in different inflammatory diseases and carcinogenesis. The precise mechanisms of these linkages are still being investigated. Also, NF-κB might even be activated by non-canonical pathways in situations where IKKβ-inhibition is delayed or inconsistent. Thus NF-κB might be differentially activated in renal cells and infiltrating inflammatory cells depending not only on the cell types but also on the progression state of the disease.
.
ABSTRACT
Glomerular diseases are often immune-mediated and the renal infiltration of leukocytes and activation of chemokines play a pivotal role in the pathogenesis of glomeruonephritis. Recent studies have uncovered that the transcription factor nuclear factor-κB (NF-κB) is a key mediator in induction of proinflammatory chemokine and cytokines gene expression in many inflammatory renal diseases. Activation of NF-κB is dependent upon the phosphorylation of its inhibitor, IκBα, by the specific inhibitory κB kinase (IKK) subunit IKKβ. We hypothesized that specific antagonism of the NF-κB inflammatory pathway through IKKβ inhibition attenuates glomerulonephritis.
Experimental nephrotoxic serum nephritis (NTN) in mice was served as a model of human rapid progressive glomerulonephritis. In the present study we first assessed the characteristics of NF-κB activation in this NTN model and found an oscillation of NF-κB activation with a first peak at day 4 after disease induction and further peaks at days 10 and 21.
To further describe the role for IKKβ-activation on the course of glomerulonephritis after NTN induction in mice a selective inhibitor of IKKβ, COMPOUND A (CpdA) was administered. After 10 days kidney function, glomerular morphology, inflammatory cells infiltration and chemokine expression were determined. Compared with untreated NTN animals the NTN mice pretreated with the IKKβ inhibitor had significant reduction in renal tissue injury. Gel shift experiment demonstrated that the translocation of NF-κB was
blocked by the IKKβ inhibitor. Interrupted or delayed IKKβ-inhibition, however, did not influence renal injury after the induction of NTN. These results therefore suggest that inhibition of IKKβ might be a potential novel therapeutic approach for patients with glomerulonephritis when applicated during the early induction period of the disease not, however, during later stages of the disease. These findings need to be confirmed in additional experimental models of renal inflammatory diseases.
ABBREVIATIONS
Ab(s) antibody
Ag antigen
ANK ankyrin repeats motifs
BAFF B-cell-activating factor of the TNF family
bp base pair
cDNA complementary DNA
Ci curie
CpdA COMPOUND A
cpm counts per minute
Cre cyclization recombination DCs dendritic cells
DNA deoxyribonucleic acid DTT dithiothreitol
EDTA ethylenediamine-N, N-tetraacetate EGTA ethylenguanidine- N, N-tetraacetate et al. Lat. et alii and others
g gram
GN glomerulonephritis
h hour (s)
HEPES N-[2-Hydroxyethyl]piperazine-N’-[2-ethanesulphonic acid]
HLH helix-loop-helix
HR homologous recombination IFN-γ interferon-gamma
Ig Immunoglobulin
IL interleukin
IκB inhibitor of NF-κB
IKK IκB kinase
LMP1 latent membrane protein-1 IP-10 interferon-inducible protein-10
kDa kilodalton
KO knockout
LPS lipopolysaccharide
LZ leucine zipper
M molar
m milli
mAb monoclonal Ab
MCAF macrophage chemotactic and activating factor MCP-1 monocyte chemoattractant protein-1
mg milligram
MHC major histocompatibility Complex
min minute(s)
ml milliliter
mM millimolar
mRNA messenger RNA
m micro
mg microgram
ml microliter
mM micromolar
MZ marginal zone
n nano
N number
NEMO NF-κB essential modulator (IKKγ) NF-κB the transcription factor nuclear factor-κB
ng nanogram
NIK NF-κB inducing kinase NLS nuclear localization signal NTN nephrotoxic serum nephritis
P phosphorylation
PBS phosphate buffered saline PCR polymerase chain reaction p- IκBα phospho- IκBα
p-p65 phospho-p65
RHD Rel-homology domain RNA ribonucleic acid
RT room temperature
RT-PCR reverse transcriptase PCR
SE standard error
Ser/S serine
SCFβTrCP Skp1-Cullin-F-box(SCF)–type TBE Tris-boric acid-EDTA
TCR T cell receptor
TEMED N, N, N’, N’ tetramethylene-diamine TLR Toll-like receptor
TNF tumor necrosis factor TNFR TNF receptor
TRAF TNFR-associated factors
U unit(s)
µl microliter
wt wild-type
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