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1.
Summary Sepsis and its potential degradation into multiple organ failure, reflects a complex immunological process occurring system
wide, fueled by local and systemic proinflammatory stimuli, the activity of which is only minimally reflected in the levels
of pro- and anti-inflammatory mediators found in the blood. On a cellular level, sepsis encompasses the up-regulation of both
pro- and anti-inflammatory pathways. Inflammation is augmented through activation of the intracellular promoter protein nuclear
factor κB (NF-κB), which induces synthesis of mRNA coding for many of the pro-inflammatory mediators, including TNF-α, IL-8, and inducible nitric oxide synthase. Similarly, the same stimuli also produce parallel activation of the heat shock
protein (hsp) pathways that inhibit NF-κB activation and minimize the inflammatory response. It is the balance between these two pathways that appears to determine
the immune responsiveness of the cells both locally and system wide. By characterizing this immune responsiveness, one may
understand better the determinants of the ultimate inflammatory response and potential immunotherapy.
Received: 7. Juli 1998 Accepted: 2 November 1998 相似文献
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SangWook Son JangHoon Lee Chan-Wook Woo IlHwan Kim YoungChul Kye KwangChul Lee JungHwa Lee 《Rheumatology international》2010,30(8):1121-1124
Autoinflammatory Blau syndrome (BS) is associated with NOD2 gene mutations that lead to constitutive NFκB activation. NOD2 functions as an intracellular receptor for the muramyl dipeptide
(MDP) component of peptidoglycan (PGN). The objectives of this study are to analyse whether NFκB activation in BS affects
immune cell functions, and whether NOD2 and toll-like receptor (TLR) pathways interact. Peripheral blood mononuclear cells
(MNCs) from a BS patient and three normal donors were analyzed for their ability to produce pro- and anti-inflammatory cytokines
in the presence and absence of MDP, PGN, and lipopolysaccharide (LPS). The results obtained showed that the basal TNF-α and
IL-10 production by MNCs over 24 h of incubation was very low for both the patient and the normal donors. However, upon stimulation
with MDP, LPS, and PGN, the cells from the BS patient produced much lower levels of TNF-α, IL-10, G-CSF, and IFN-γ than the
normal donor cells. We conclude that the pathogenic mechanism responsible for the chronic inflammation that characterizes
BS may relate to the impaired production of both pro- and anti-inflammatory cytokines to stimuli. The NOD2 pathway possibly
interacts with either the TLR2 or TLR4 pathways. 相似文献
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Yaou Zhou Xiaoxia Zuo Yisha Li Yanping Wang Hongjun Zhao Xianzhong Xiao 《Rheumatology international》2012,32(1):97-104
It was recently demonstrated that the cholinergic anti-inflammatory pathway can modulate host inflammatory responses via cholinergic
mediators or via electrical stimulation of the vagus nerve. Here, we investigated whether nicotine, a selective cholinergic
agonist, plays any anti-inflammatory role in rheumatoid arthritis fibroblast-like synoviocytes (FLS). We observed that low
concentrations (0.1–100 μM) of nicotine did not affect FLS viability in lactate dehydrogenase release test or the MTT assay.
Nicotine at concentrations of 0.1–10 μM dose reduced the protein and mRNA expression of IL-6 and IL-8 induced by tumor necrosis
factor-α (TNFα). Nicotine also inhibited nuclear factor (NF)-κB (p65) translocation from the cytoplasm to the nucleus, based
on Western blotting and immunocytochemical analysis. In conclusion, nicotine can inhibit the TNFα dependant inflammatory pathway
in synoviocytes by suppressing the activation of the NF-κB pathway. 相似文献
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Haobo Lin Youjun Xiao Guoqiang Chen Di Fu Yujin Ye Liuqin Liang Jinjin Fan Xiuyan Yang Lin Sun Hanshi Xu 《Rheumatology international》2011,31(11):1451-1458
To investigate whether anti-inflammatory effects of HMG-CoA reductase inhibitor simvastatin (SMV) in rheumatoid arthritis
(RA) is mediated by Toll-like receptor-2 (TLR-2) signal via inhibiting activation of RhoA, a small Rho GTPase that plays an
important role in inflammatory responses. Peripheral blood monocytes from active RA patients were treated with Staphylococcus aureus peptidoglycan (PG), a ligand of TLR-2, in the presence or absence of SMV. RhoA activity was assessed by a pull-down assay. DNA-binding activity was measured by a sensitive multi-well colorimetric assay. Cytokine secretion was measured by
ELISA. PG stimulation increased the level of active GTP-bound RhoA compared with unstimulated monocytes, and the effect of
PG on RhoA activity was suppressed with anti-TLR-2 monoclonal antibody. RhoA inhibition either with a specific inhibitor or
by siRNA transfection inhibited activation of NF-κB and secretion of TNFα and IL-1β in PG-induced RA monocytes. SMV mitigated
PG-induced increase in RhoA activity and NF-κB activation as well as secretion of TNFα and IL-1β. The inhibitory effects of
SMV were completely reversed by mevalonate and geranylgeranyl pyrophosphate. Our results indicate the modulation of RhoA on
TLR-2-mediated inflammatory signaling in RA and provide a novel evidence for anti-inflammatory effects of statins through
influencing TLR-2 signaling via RhoA in RA. 相似文献
7.
This study was designed to determine levels of NF-κB reporter gene activity and free radical generation in cultured striated
myocytes (H9C2 cells) exposed to cocaine or morphine in the presence of free radical scavengers. Cells were transiently transfected
with a NF-κB reporter gene and changes in luciferase activity were detected, by bioluminescence. Using confocal microscopy
and 2′,7′-dichlorofluorescin diacetate, cocaine-induced or morphine-induced free radicals were quantified in H9C2 cells. Cocaine
and morphine (0–1×10−2
M) were tested separately. Cocaine but not morphine significantly activated Nf-κB reporter gene, activity in H9C2 cells. Overexpression
of IκB inhibited NF-κB reporter activity at low (1×10−4
M) but not high (1×10−2
M) cocaine concentrations. Free radicals were generated in H9C2 cells stimulated with cocaine but not with morphine. The production
of free radicals and NF-κB reporter gene activity could be blocked with N-acetylcysteine, glutathione, and to a lesser extent, lipoic acid. The results suggest that cocaine induces free radical production,
which leads to the activation of NF-κB signal transduction and possible inflammatory responses. 相似文献
8.
Steroid resistance in asthma: Mechanisms and treatment options 总被引:1,自引:0,他引:1
Glucocorticoid insensitivity presents a profound management problem in patients with asthma because conventional therapies
are not effective. Glucocorticoids, acting through the glucocorticoid receptor (GR), are able to selectively repress inflammatory
gene expression by utilizing several distinct mechanisms targeting nuclear factor-κB and activator protein-1 activation complexes
and by effects on mitogen-activated protein kinases. Different model systems often activate distinct sets of signaling molecules
and different glucocorticoid responsiveness may result from differences in concentrations and timing of steroid treatment
of cells, GR expression levels, and the precise inflammatory stimulus used. Thus, abnormal activation of many signaling pathways
may affect corticosteroid responsiveness in patients with corticosteroid-resistant asthma. Understanding the molecular mechanisms
of GR action and inaction may lead to the development of new anti-inflammatory drugs or enable clinicians to reverse the relative
steroid-insensitivity that is characteristic of some patients with severe asthma. 相似文献
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Background and aims The involvement of bacteria in the pathogenesis of inflammatory bowel disease has been discussed for several years. In this study we evaluated the ability of E. coli isolates from inflamed and noninflamed colonic mucosa to activate NF-B.Materials and methods Fifteen bacterial strains from inflamed and six from noninflamed colonic tissues from IBD patients. Their ability to induce NF-B activation was examined in vitro by gel-shift assays. The activation of the TNF- promoter was determined by reporter gene assays. Bacterial isolates were characterized by invasion assays, electron microscopy, and PCR.Results Four of 15 E. coli bacterial isolates from inflamed IBD tissues induced NF-B activity in intestinal epithelial cells as determined by gel-shift assays. NF-B activation was only seen with living bacteria but not with heat-inactivated cells. Isolates from noninflamed tissues and a wild-type E. coli control strain induced a weaker or no activation. Reporter gene assays with a construct comprising a luciferase gene driven by the TNF- promoter revealed that isolates from Crohns disease patients induced a stronger activation of the TNF- gene than isolates from ulcerative colitis patients. The isolated bacteria invaded HT-29 cells, although typical virulence genes for enteropathogenic, enterhemorrhagic, or enteroinvasive E. coli, i.e., eae, tir, EspA, Per (A-C), ipaC, were not detected in these cells. Bacterial invasion was additionally confirmed by electron microscopy examination.Conclusion Our results indicate that E. coli strains can be found in the mucosa of some IBD patients which are able to activate NF-B similar to known pathogenic strains. The absence of several virulence genes in these cells suggests that they are members of the luminal flora which acquire as yet unidentified virulence determinants and are therefore involved in the pathophysiology of IBD. 相似文献
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Eun-Ha Joh In-Ah Lee Sang-Jun Han SunJu Chae Dong-Hyun Kim 《International journal of colorectal disease》2010,25(5):545-551
Purpose
In a preliminary study, we found that lancemaside A, which is a main constituent of Codonopsis lanceolata used as an herbal medicine for inflammatory diseases, potently inhibits lipopolysaccharide (LPS)-stimulated, TLR-4-linked NF-κB activation of NF-κB luciferase reporter gene-transfected 293-hTLR4-hemagglutinin (HA) cells. Therefore, we investigated its inhibitory effect in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in mice. 相似文献15.
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Exclusive enteral nutrition using polymeric formula (PF) is a well-established therapeutic option for active Crohn’s disease;
however, its mechanisms of action are unknown. We investigated the anti-inflammatory effects of PF in an in vitro model of
epithelial cell inflammation. PF did not affect cell viability over a range of dilutions, but when PF was added to the culture
medium the interleukin (IL)-8 response to proinflammatory stimuli was significantly reduced. This effect was due to PF acting
directly on the cells as the IL-8 response was still reduced when PF was separated from the proinflammatory stimuli in a 2-compartment
system. In the presence of PF, nuclear factor (NF)-κB nuclear migration was not inhibited; however, IκBα degradation was delayed.
PF has direct anti-inflammatory effects upon immortalized colonic enterocytes. Therefore PF may, in part, modulate gut inflammation
by directly reducing the inflammatory response of the intestinal epithelium. 相似文献
19.
Garlie JB Hamid T Gu Y Ismahil MA Chandrasekar B Prabhu SD 《Basic research in cardiology》2011,106(6):1193-1205
The in vivo role of TNF signaling in the genesis of β-adrenergic receptor (β-AR)-mediated cardiac hypertrophy is unknown.
Wild-type (WT), TNF receptor 1 (TNFR1)-/- and TNFR2-/- mice were given isoproterenol (ISO, 12.5 μg/kg/h) or saline (SAL) for
1 or 7 days. In WT mice, 7 days of ISO yielded chamber/myocyte hypertrophy and hyperdynamic function without hypertension
or fibrosis. WT ISO hearts exhibited an early (1 day) pro-inflammatory response with significant (p < 0.05) activation of nuclear factor (NF)-κB and activator protein 1 (AP-1) and upregulation of TNF, interleukin (IL)-1β
and IL-6, inducible nitric oxide synthase (iNOS) and monocyte chemotactic protein-1 (MCP-1), together with increased anti-inflammatory
IL-10. This response diminished markedly by 7 days. As compared with WT ISO mice, TNFR1-/- ISO mice exhibited significantly
(p < 0.05) less NF-κB and AP-1 activation, less IL-1β, TNF, iNOS and MCP-1 upregulation, but greater IL-10 at 1 day. However,
there were no differences in hypertrophy or contractility at 7 days. In contrast, TNFR2-/- ISO mice exhibited augmented NF-κB
and AP-1 activation, increased IL-1β and diminished IL-10 expression at 1 day, and significant exaggeration of hypertrophy
and less contractile augmentation at 7 days. Moreover, TNFR2-/- mice exposed to tenfold higher ISO doses displayed significant
mortality. TNF signaling contributes to β-AR-mediated cardiac remodeling in vivo in a receptor-specific manner. Unopposed
TNFR1 activation is pro-inflammatory, pro-hypertrophic and promotes functional decline. However, co-activation of TNFR2 during
β-AR stress is anti-inflammatory and counterbalances these deleterious effects. TNF modulatory strategies that maintain TNFR2
signaling may help prevent the detrimental long-term effects of β-AR stimulation in the heart. 相似文献
20.
Ka SM Yeh YC Huang XR Chao TK Hung YJ Yu CP Lin TJ Wu CC Lan HY Chen A 《Diabetologia》2012,55(2):509-519