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3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been shown to reduce the progression of renal disease
independent of cholesterol-lowering effect, but the mechanism of potential protective effect remains unclear. Here, we investigate
the effect of fluvastatin on activation of nuclear factor-κB (NF-κB) induced by angiotensin II (AngII) in rat kidney tubule
epithelial cells (NRK-52E). Electrophoretic mobility shift assays (EMSA) was used to detect NF-κB activation. Phosphorylation
of cellular p38 mitogen-activated protein kinase (p38MAPK) was determined by western blot analysis. AngII stimulated the DNA-binding
activity of NF-κB and phosphorylation of p38MAPK in cultured NRK-52E cells in a dose-dependent (10−9–10−6 mol/l) manner (P < 0.01). AngII (10−6 mol/l) induced a rapid (5 min) increase of the p38MAPK phosphorylation. NF-κB DNA-binding activity was increased at as early
as 30 min, peaked at 2 h after AngII treatment. This stimulatory effect of AngII on NF-κB was blocked by SB203580 (a specific
inhibitor of p38MAPK). Incubation of cells with fluvastatin significantly inhibited the AngII-induced NF-κB activation in
a dose-dependent (10−7–10−5 mol/l) manner (P < 0.05). Exogenous mevalonate (10−4mol/l) prevented the effect of fluvastatin on NF-κB activation. These results suggest the fluvastatin reduced AngII-induced
NF-κB activation via the p38MAPK pathway in NRK-52E cells. The effect is at least partly due to blocking the biosynthesis
of mevalonate. 相似文献
3.
Sander W Tas Margriet J Vervoordeldonk Najat Hajji Michael J May Sankar Ghosh Paul P Tak 《Arthritis research & therapy》2006,8(4):R86-9
Nuclear factor (NF)-κB is a key regulator of synovial inflammation. We investigated the effect of local NF-κB inhibition in
rat adjuvant arthritis (AA), using the specific IκB kinase (IKK)-β blocking NF-κB essential modulator-binding domain (NBD)
peptide. The effects of the NBD peptide on human fibroblast-like synoviocytes (FLS) and macrophages, as well as rheumatoid
arthritis (RA) whole-tissue biopsies, were also evaluated. First, we investigated the effects of the NBD peptide on RA FLS
in vitro. Subsequently, NBD peptides were administered intra-articularly into the right ankle joint of rats at the onset of disease.
The severity of arthritis was monitored over time, rats were sacrificed on day 20, and tissue specimens were collected for
routine histology and x-rays of the ankle joints. Human macrophages or RA synovial tissues were cultured ex vivo in the presence or absence of NBD peptides, and cytokine production was measured in the supernatant by enzyme-linked immunosorbent
assay. The NBD peptide blocked interleukin (IL)-1-β-induced IκBα phosphorylation and IL-6 production in RA FLS. Intra-articular
injection of the NBD peptide led to significantly reduced severity of arthritis (p < 0.0001) and reduced radiological damage (p = 0.04). This was associated with decreased synovial cellularity and reduced expression of tumor necrosis factor (TNF)-α
and IL-1-β in the synovium. Incubation of human macrophages with NBD peptides resulted in 50% inhibition of IL-1-β-induced
TNF-α production in the supernatant (p < 0.01). In addition, the NBD peptide decreased TNF-α-induced IL-6 production by human RA synovial tissue biopsies by approximately
42% (p < 0.01). Specific NF-κB blockade using a small peptide inhibitor of IKK-β has anti-inflammatory effects in AA and human RA
synovial tissue as well as in two important cell types in the pathogenesis of RA: macrophages and FLS. These results indicate
that IKK-β-targeted NF-κB blockade using the NBD peptide could offer a new approach for the local treatment of arthritis. 相似文献
4.
Increased bone resorption mediated by osteoclasts causes various diseases such as osteoporosis and bone erosion in rheumatoid
arthritis (RA). Osteoclasts are derived from the monocyte/macrophage lineage, but the precise origin remains unclear. In the
present study, we show that the purified CD16- human peripheral blood monocyte subset, but not the CD16+ monocyte subset, differentiates into osteoclast by stimulation with receptor activator of NF-κB ligand (RANKL) in combination
with macrophage colony-stimulating factor (M-CSF). Integrin-β3 mRNA and the integrin-αvβ3 heterodimer were only expressed
on CD16- monocytes, when they were stimulated with RANKL + M-CSF. Downregulation of β3-subunit expression by small interfering RNA
targeting β3 abrogated osteoclastogenesis from the CD16- monocyte subset. In contrast, the CD16+ monocyte subset expressed larger amounts of tumor necrosis factor alpha and IL-6 than the CD16- subset, which was further enhanced by RANKL stimulation. Examination of RA synovial tissue showed accumulation of both CD16+ and CD16- macrophages. Our results suggest that peripheral blood monocytes consist of two functionally heterogeneous subsets with distinct
responses to RANKL. Osteoclasts seem to originate from CD16- monocytes, and integrin β3 is necessary for osteoclastogenesis. Blockade of accumulation and activation of CD16- monocytes could therefore be a beneficial approach as an anti-bone resorptive therapy, especially for RA. 相似文献
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Dendritic cells are the major antigen-presenting and antigen-priming cells of the immune system. We review the antigen-presenting
and proinflammatory roles played by dendritic cells in the initiation of rheumatoid arthritis (RA) and atherosclerosis, which
complicates RA. Various signals that promote the activation of NF-κB and the secretion of TNF and IL-1 drive the maturation
of dendritic cells to prime self-specific responses, and drive the perpetuation of synovial inflammation. These signals may
include genetic factors, infection, cigarette smoking, immunostimulatory DNA and oxidized low-density lipoprotein, with major
involvement of autoantibodies. We propose that the pathogenesis of RA and atherosclerosis is intimately linked, with the vascular
disease of RA driven by similar and simultaneous triggers to NF-κB. 相似文献
6.
Patients with rheumatoid arthritis (RA) and osteoarthritis (OA) consume 'natural health products' (NHPs) whose therapeutic
efficacy, toxicity and mechanisms of action are poorly understood. In a previous issue of Arthritis Research and Therapy, Haqqi and colleagues characterized IL-1-activated mitogen-activated protein kinase kinase 3 (MKK3) and p38-mitogen-activated
protein kinase (MAPK) isoforms in human OA chondrocytes. The cartilageprotective mechanisms of pomegranate extract involve
diminishing MKK3-activated p38α, JNK, NF-κB and Runx2 pathways, which regulate inflammatory proteins and cartilage-destroying
proteases. Epigallocatechin- 3-gallate, resveratrol, curcumin and other NHP active ingredients suppress multiple inflammatory
and catabolic molecular mediators of arthritis. Non-toxicity, reduced severity and incidence of arthritis in animal models
warrant testing NHP active ingredients for preventing human OA and RA. 相似文献
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Bae S Kim H Lee N Won C Kim HR Hwang YI Song YW Kang JS Lee WJ 《Journal of immunology (Baltimore, Md. : 1950)》2012,189(1):365-372
α-Enolase (ENO1) is a multifunctional glycolytic enzyme expressed abundantly in the cytosol. It has been implicated in autoimmune and inflammatory diseases. Serum Abs against ENO1 were reported in rheumatoid arthritis (RA). Cell-surface expression of ENO1 has been found to be increased rapidly in response to inflammatory stimuli, but its expression and function has not been reported in RA. In this study, we show that cell-surface expression of ENO1 is increased on monocytes and macrophages isolated from RA patients but not on those from osteoarthritis patients, and Ab against ENO1 can stimulate these cells to produce higher amounts of proinflammatory mediators, such as TNF-α, IL-1 α/β, IFN-γ, and PGE(2) via p38 MAPK and NF-κB pathway. The frequency of ENO1-positive cells in synovial fluid mononuclear cells was higher than PBMCs. ENO1-positive cells were also found in the inflamed synovium from RA patients and arthritic ankle tissues of mice with collagen-induced arthritis. Taken together, these findings suggest that Abs against ENO1 present in RA sera may stimulate monocytes and macrophages expressing cell-surface ENO1 and contribute to production of proinflammatory mediators during the effector phase of synovial inflammation. 相似文献
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Tetsuo Kubota Machiko Hoshino Kazuhiro Aoki Keiichi Ohya Yukiko Komano Toshihiro Nanki Nobuyuki Miyasaka Kazuo Umezawa 《Arthritis research & therapy》2007,9(5):R97
Inhibition of NF-κB is known to be effective in reducing both inflammation and bone destruction in animal models of arthritis.
Our previous study demonstrated that a small cell-permeable NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), suppresses
expression of proinflammatory cytokines and ameliorates mouse arthritis. It remained unclear, however, whether DHMEQ directly
affects osteoclast precursor cells to suppress their differentiation to mature osteoclasts in vivo. The effect of DHMEQ on human osteoclastogenesis also remained elusive. In the present study, we therefore examined the effect
of DHMEQ on osteoclastogenesis using a mouse collagen-induced arthritis model, and using culture systems of fibroblast-like
synovial cells obtained from patients with rheumatoid arthritis, and of osteoclast precursor cells from peripheral blood of
healthy volunteers. DHMEQ significantly suppressed formation of osteoclasts in arthritic joints, and also suppressed expression
of NFATc1 along the inner surfaces of bone lacunae and the eroded bone surface, while serum levels of soluble receptor activator
of NF-κB ligand (RANKL), osteoprotegerin and macrophage colony-stimulating factor were not affected by the treatment. DHMEQ
also did not suppress spontaneous expression of RANKL nor of macrophage colony-stimulating factor in culture of fibroblast-like
synovial cells obtained from patients with rheumatoid arthritis. These results suggest that DHMEQ suppresses osteoclastogenesis
in vivo, through downregulation of NFATc1 expression, without significantly affecting expression of upstream molecules of the RANKL/receptor
activator of NF-κB/osteoprotegerin cascade, at least in our experimental condition. Furthermore, in the presence of RANKL
and macrophage colony-stimulating factor, differentiation and activation of human osteoclasts were also suppressed by DHMEQ,
suggesting the possibility of future application of NF-κB inhibitors to rheumatoid arthritis therapy. 相似文献
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Kyoko Wakamatsu Toshihiro Nanki Nobuyuki Miyasaka Kazuo Umezawa Tetsuo Kubota 《Arthritis research & therapy》2005,7(6):R1348
A small cell-permeable compound, dehydroxymethylepoxyquinomicin (DHMEQ), does not inhibit phosphorylation and degradation
of IκB (inhibitor of nuclear factor-κB [NF-κB]) but selectively inhibits nuclear translocation of activated NF-κB. This study
aimed to demonstrate the antiarthritic effect of this novel inhibitor of the NF-κB pathway in vivo in a murine arthritis model and in vitro in human synovial cells. Collagen-induced arthritis was induced in mice, and after onset of arthritis the mice were treated
with DHMEQ (5 mg/kg body weight per day). Using fibroblast-like synoviocyte (FLS) cell lines established from patients with
rheumatoid arthritis (RA), NF-κB activity was examined by electrophoretic mobility shift assays. The expression of molecules
involved in RA pathogenesis was determined by RT-PCR, ELISA, and flow cytometry. The proliferative activity of the cells was
estimated with tritiated thymidine incorporation. After 14 days of treatment with DHMEQ, mice with collagen-induced arthritis
exhibited decreased severity of arthritis, based on the degree of paw swelling, the number of swollen joints, and radiographic
and histopathologic scores, compared with the control mice treated with vehicle alone. In RA FLS stimulated with tumor necrosis
factor-α, activities of NF-κB components p65 and p50 were inhibited by DHMEQ, leading to suppressed expression of the key
inflammatory cytokine IL-6, CC chemokine ligand-2 and -5, matrix metalloproteinase-3, intercellular adhesion molecule-1, and
vascular cell adhesion molecule-1. The proliferative activity of the cells was also suppressed. This is the first demonstration
of an inhibitor of NF-κB nuclear translocation exhibiting a therapeutic effect on established murine arthritis, and suppression
of inflammatory mediators in FLS was thought to be among the mechanisms underlying such an effect. 相似文献
12.
Changes in the levels of antiapoptotic protein B-cell lymphoma 2 (Bcl-2) protein has been reported in murine and human tuberculosis.
We investigated the role of mitogen-activated protein kinase pathways in the production of Bcl-2 protein in THP-1 human monocytes
infected with Mycobacterium tuberculosis H37Rv and H37Ra. Analysis of phosphorylation profiles of mitogen-activated protein kinase kinase-1, extracellular-signal
regulated kinase 1/2, mitogen-activated protein kinase kinase 3/6, and p38 mitogen-activated protein kinase; B-cell lymphoma
2 kinetics; and tumor necrosis factor-α (TNF-α) secretion levels showed variation between the two strains. Mycobacterium tuberculosis H37Rv induced higher Bcl-2 and lower TNF-α levels, whereas H37Ra the reverse. The strains also differed in their usage of
CD14 and human leukocyte antigen-DR receptors in mediating extracellular-signal regulated kinase 1/2 and p38 mitogen-activated
protein kinase activation. Mycobacterium tuberculosis H37Rv- and H37Ra-induced Bcl-2 production was reduced by specific inhibitors of mitogen-activated protein kinase kinase-1
(PD98059) and p38 (SB203580), but increased by nuclear factor κB (NF-κB) inhibitor (BAY 11-7082). TNF-α production by both
strains was reduced in the presence of specific inhibitors of mitogen-activated protein kinase kinase-1 (PD98059), p38 (SB203580),
and NF-κB (BAY 11-7082). Furthermore, inhibition of NF-κB was accompanied by an increase in strain-induced extracellular-signal
regulated kinase 1/2 phosphorylation. Collectively, these results indicate for the first time that the production of Bcl-2
and TNF-α by M. tuberculosis H37Rv/H37Ra-infected THP-1 human monocytes is mediated through mitogen-activated protein kinases and NF-κB. 相似文献
13.
The LAIR-1 receptor is expressed on a majority of mononuclear leukocytes. It is used as a biomarker when testing synovial fluid for evidence of rheumatoid arthritis (RA). The primary objective of this study was to measure T cell- and monocyte/macrophage-specific LAIR-1 expression in RA patients and compare this to LAIR-1 expression in osteoarthritis (OA) patients and healthy individuals. LAIR-1 expression was significantly decreased in circulating CD4+ T cells in RA patients compared to both OA patients and healthy individuals. In contrast, LAIR-1 is high in CD14+ monocytes and local CD68+ macrophages in synovial tissues from RA patients. Upon stimulation with TNF-α, LAIR-1 expression decreased in T-helper (Th)1 and Th2 CD4+ T cells from healthy donors. These results indicate that LAIR-1 may exert different functions on T cells and monocytes/macrophages and suggest that LAIR-1 may be a novel therapeutic target for the treatment of RA. 相似文献
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Ceramide causes either apoptosis or non-apoptotic cell death depending on model system and experimental conditions. The present
study was undertaken to examine the effect of ceramide on cell viability and its molecular events leading to cell death in
A172 human glioma cells. Ceramide induced cell death in a dose-dependent manner and the cell death was dependent on generation
of reactive oxygen species and lipid peroxidation. TUNEL assay, Hoechst 33258 staining, and flow cytometric analysis did not
show typical apoptotic morphological features. Ceramide caused phosphorylation of extracellular signal-regulated kinase (ERK)
and p38, but the cell death was not affected by inhibitors of MAPK subfamilies. Ceramide caused ATP depletion without loss
of mitochondrial membrane potential. Ceramide did not induce caspase activation and ceramide-induced cell death was also not
altered by inhibitors of caspase activation. Transfection of dominant inhibitory mutant of IκBα (S32A/36A) and pretreatment
of pyrrolidinedithiocarbamate, an inhibitor of NF-κB, enhanced ceramide-induced cell death. These results indicate that ceramide
causes non-apoptotic, caspase-independent cell death by inducing reactive oxygen species generation in A172 human glioma cells.
NF-κB is involved in the regulation of ceramide-induced cell death in human glioma cells. 相似文献
16.
Background
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the synovial joints. Early intervention followed by early diagnosis can result in disease remission; however, both early stage diagnosis and provision of effective treatment have been impeded by the heterogeneity of RA, which details of pathological mechanism are unclear. Regardless of numerous investigations of RA by means of genomic and proteomic approaches, proteins interplaying in RA synovial tissues that contain various types of synoviocytes, are not yet sufficiently understood. Hence we have conducted an HPLC/mass spectrometry-based exploratory proteomic analysis focusing on synoviocyte lesions laser-microdissected (LMD) from formalin-fixed paraffin-embedded (FFPE) synovial tissues (RA, n = 15; OA, n = 5), where those of Osteoarthritis (OA) were used as the control.Results
A total of 508 proteins were identified from the RA and OA groups. With the semi-quantitative comparisons, the spectral index (SpI), log2 protein ratio (RSC) based on spectral counting, and statistical G-test, 98 proteins were found to be significant (pair-wise p < 0.05) to the RA synovial tissues. These include stromelysin-1 (MMP3), proteins S100-A8 and S100-A9, plastin-2, galectin-3, calreticulin, cathepsin Z, HLA-A, HLA-DRB1, ferritin, neutrophil defensin 1, CD14, MMP9 etc.Conclusions
Our results confirmed the involvement of known RA biomarkers such as stromelysin-1 (MMP3) and proteins S100-A8 and S100-A9, and also that of leukocyte antigens such as HLA-DRB1. Network analyses of protein–protein interaction for those proteins significant to RA revealed a dominant participation of ribosome pathway (p = 5.91 × 10−45), and, interestingly, the associations of the p53 signaling (p = 2.34 × 10−5). An involvement of proteins including CD14, S100-A8/S100-A9 seems to suggest an activation of the NF-kB/MAPK signaling pathway. Our strategy of laser-microdissected FFPE-tissue proteomic analysis in Rheumatoid Arthritis thus demonstrated its technical feasibility in profiling proteins expressed in synovial tissues, which may play important roles in the RA pathogenesis.Electronic supplementary material
The online version of this article (doi:10.1186/s12014-015-9091-8) contains supplementary material, which is available to authorized users. 相似文献17.
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Jia-He Wang Bo Yu Ping He Xue Bai 《World journal of microbiology & biotechnology》2011,27(8):1827-1838
We previously showed that infection of human monocytic U937 cells with nonpathogenic Escherichia coli (E. coli) induced rapid apoptosis in a dose- and time-dependent manner. We also found that E. coli increase p38 mitogen-activated protein Kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK), and decrease extracellular-Regulated
Kinase1/2 (ERK1/2) phosphorylation and increase caspase-3 and -9 activity in U937 cells. The current study determines if Bcl-2,
Bax, the phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor kappa B (NF-κB) regulates E. coli–induced U937 cell apoptosis. Studying the underlying mechanisms we found that the E. coli-induced apoptosis in U937 cells was associated with a more prominent reduction in expression of Bcl-2, levels of P-Akt and
NF-κB. Because levels of inhibition of apoptosis protein (cIAP), and X-chromosomelinked inhibitor of apoptosis protein (XIAP)
are regulated by NF-κB, E. coli decreased the levels of these proteins in U937 cells through inhibition of NF-κB. Moreover, E. coli markedly elevated Bax expression and cytochrome c redistribution. LY294002, PDTC and Embelin, specific inhibitors of PI3K, NF-κB and XIAP, induced U937 cell apoptosis and
the apoptosis is dependent on activity of caspase-3 and -9 in E. coli-treated U937 cells. Through using LY294002 and western blotting, we identified NF-κB was the downstream Akt target regulated
by E. coli. Taken together, these results clearly indicate reduced activation of NF-κB via impaired PI3K/Akt activation could result
in increased apoptosis of U937 cells infected by E. coli. Moreover, E. coli can induce apoptosis with an increased expression of Bax and a reduced expression of Bcl-2, which resulted in increased levels
of cytochrome c release and increase caspase-3 and -9 in U937 cells. 相似文献
19.
Takasugi K Yamamura M Iwahashi M Otsuka F Yamana J Sunahori K Kawashima M Yamada M Makino H 《Arthritis research & therapy》2006,8(4):R126-13
Despite its potent ability to inhibit proinflammatory cytokine synthesis, interleukin (IL)-10 has a marginal clinical effect
in rheumatoid arthritis (RA) patients. Recent evidence suggests that IL-10 induces monocyte/macrophage maturation in cooperation
with macrophage-colony stimulating factor (M-CSF). In the present study, we found that the inducible subunit of the IL-10
receptor (IL-10R), type 1 IL-10R (IL-10R1), was expressed at higher levels on monocytes in RA than in healthy controls, in
association with disease activity, while their expression of both type 1 and 2 tumour necrosis factor receptors (TNFR1/2)
was not increased. The expression of IL-10R1 but not IL-10R2 was augmented on monocytes cultured in the presence of RA synovial
tissue (ST) cell culture supernatants. Cell surface expression of TNFR1/2 expression on monocytes was induced by IL-10, and
more efficiently in combination with M-CSF. Two-color immunofluorescence labeling of RA ST samples showed an intensive coexpression
of IL-10R1, TNFR1/2, and M-CSF receptor in CD68+ lining macrophages. Adhered monocytes, after 3-day preincubation with IL-10 and M-CSF, could produce more IL-1β and IL-6
in response to TNF-α in the presence of dibutyryl cAMP, as compared with the cells preincubated with or without IL-10 or M-CSF
alone. Microarray analysis of gene expression revealed that IL-10 activated various genes essential for macrophage functions,
including other members of the TNFR superfamily, receptors for chemokines and growth factors, Toll-like receptors, and TNFR-associated
signaling molecules. These results suggest that IL-10 may contribute to the inflammatory process by facilitating monocyte
differentiation into TNF-α-responsive macrophages in the presence of M-CSF in RA. 相似文献