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1.
The pro-inflammatory cytokines IL-6 and TNF-alpha have been implicated in the pathogenesis of otitis media with effusion (OME). A disease where goblet cells proliferate in a modified respiratory epithelium, leading to the accumulation of a mucin-rich effusion in the middle ear cleft. The MUC5AC and MUC5B mucin gene products have been identified as components of these effusions. To determine the effect of IL-6 and TNF-alpha on MUC5AC and MUC5B secretion we have used HT29-MTX goblet cells, which secrete both types of mucins. MUC5AC and MUC5B mucin secretion was measured by an enzyme-linked immunosorbent assay (ELISA) using a specific monoclonal antibody NCL-HGM-45M1 and polyclonal antiserum TEPA, respectively. Time response (0-72 hours) and dose response (1.5-150 ng/ml) studies were carried out. IL-6 and TNF-alpha stimulated MUC5AC and MUC5B mucin secretion in a time dependent manner, both in pre-confluent and post-confluent cells. IL-6 (15 ng/ml and 20 ng/ml) produced a low and prolonged stimulation of mucin secretion that persisted for 72 hours, with peak response at 24 hours after induction. The IL-6-mediated mucin secretion at 24 hours was concentration-dependent, with a maximal effect at 15 ng/ml. TNF-alpha (20 ng/ml) induced rapid stimulation of mucin secretion within the first 24 hours, with peak response at 7 hours after induction. IL-6 and TNF-alpha exposure significantly increased MUC5AC secretion, but not MUC5B secretion. Maximal levels of cytokine-induced mucin secretion were detected in pre-confluent cells that showed one and a half- and two-fold increases in MUC5AC secretion after IL-6 and TNF-alpha stimulation, respectively, in comparison with post-confluent cells. The results presented here suggest that IL-6 and TNF-alpha generate a differential up-regulation of mucin secretion and thus contribute to the expression of mucin genes in inflammatory responses. 相似文献
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G. van Luijtelaar S. Lyashenko R. Vastyanov G. Verbeek A. Oleinik C. van Rijn G. Volokhova A. Shandra A. Coenen L. Godlevsky 《Neurophysiology》2012,43(6):478-486
We investigated the role of two cytokines, IL-1β and TNF-α, in the development of absence seizures using a genetic model of
absence epilepsy in WAG/Rij rats. We administered these cytokines to animals systemically and measured the number of spike-wave
discharges (SWDs) in the EEG. We also coadministered IL-1β with the GABA reuptake inhibitor tiagabine and measured the levels
of IL-1β and TNF-α in the brain and blood plasma of 2-, 4-, and 6-month-old WAG/Rij rats and animals that served as a non-epileptic
control (ACI). We found that IL-1β induced a significant increase in SWDs 2-5 h after administration, while TNF-α enhanced
SWDs much later. Both cytokines enhanced passive behavior; body temperature was elevated only after TNF-α. The action of tiagabine
was potentiated by earlier IL-1β injection, even when IL-1β was no longer active. Young WAG/Rij rats showed higher levels
of TNF-α in blood serum than young ACI rats; the effects in the brain tended to be opposite. The marked differences in timing
of the increase in SWDs suggest different time scales for the action of both cytokines tested. It is proposed that the results
found after TNF-α are due to the de novo synthesis of IL-1β. TNF-α may possess neuroprotective effects. IL-1β might increase GABA-ergic neurotransmission. The changes
in the efficacy of antiepileptic drugs related to changes in the cytokine systems may have some clinical relevance. 相似文献
4.
Birk Poller Jürgen Drewe Stephan Krähenbühl Jörg Huwyler Heike Gutmann 《Cellular and molecular neurobiology》2010,30(1):63-70
Brain capillary endothelial cells form the blood–brain barrier (BBB), a highly selective permeability membrane between the
blood and the brain. Besides tight junctions that prevent small hydrophilic compounds from passive diffusion into the brain
tissue, the endothelial cells express different families of drug efflux transport proteins that limit the amount of substances
penetrating the brain. Two prominent efflux transporters are the breast cancer resistance protein and P-glycoprotein (P-gp).
During inflammatory reactions, which can be associated with an altered BBB, pro-inflammatory cytokines are present in the
systemic circulation. We, therefore, investigated the effect of the pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6
(IL-6) and tumor necrosis factor-α (TNF-α) on the expression and activity of BCRP and P-gp in the human hCMEC/D3 cell line.
BCRP mRNA levels were significantly reduced by IL-1β, IL-6 and TNF-α. The strongest BCRP suppression at the protein level
was observed after IL-1β treatment. IL-1β, IL-6 and TNF-α also significantly reduced the BCRP activity as assessed by mitoxantrone
uptake experiments. P-gp mRNA levels were slightly reduced by IL-6, but significantly increased after TNF-α treatment. TNF-α
also increased protein expression of P-gp but the uptake of the P-gp substrate rhodamine 123 was not affected by any of the
cytokines. This in vitro study indicates that expression levels and activity of BCRP, and P-gp at the BBB may be altered by
acute inflammation, possibly affecting the penetration of their substrates into the brain. 相似文献
5.
S. J. D. Vitkus S. A. Hanifin D. W. McGee 《In vitro cellular & developmental biology. Animal》1998,34(8):660-664
Summary Intestinal epithelial cells (IEC) have previously been shown to produce several cytokines including interleukin-6 (IL-6).
However, many factors which may regulate IL-6 secretion by human IEC still remain a mystery due in part to the lack of appropriate
model cell lines and the difficulty of culturing human IEC over long periods of time. We have determined that the human colonic
carcinoma cell line Caco-2 is capable of secreting IL-6 when stimulated by the inflammatory cytokines IL-1β or tumor necrosis
factor-α (TNF-α), and stimulation of these cells with IL-1β plus TNF-α induced a synergistic enhancement of IL-6 secretion.
The inflammatory cytokine-induced enhancement in IL-6 secretion was greatest when the cells were cultured in a 10% CO2 atmosphere as compared to cells grown in 5% CO2, suggesting that environmental CO2 levels may affect IEC cytokine secretion. Finally, long-term culture of the Caco-2 cells to induce cellular differentiation
had no effect on the capacity of these cells to produce IL-6, indicating that the regulation of IL-6 secretion was not affected
by differentiation. Taken together, these studies provide important information on the factors which regulate IL-6 secretion
by human IEC as they may contribute to the cytokine network during a mucosal inflammation. The results also suggest that the
Caco-2 cell line is an appropriate model for further studies on the regulation of cytokine secretion by human IEC. 相似文献
6.
LPS up-regulates mucin and cytokine mRNA expression and stimulates mucin and cytokine secretion in goblet cells 总被引:21,自引:0,他引:21
Bacterial inflammation in mucosa is accompanied by morphological and proliferative changes in goblet cells and mucin hypersecretion. Main stimulators of bacterial inflammation are bacterial lipopolysaccharides (LPS). In vitro investigation of the LPS effect on the molecular processes in goblet cells, using the human mucin-secreting goblet cell line HT29-MTX, showed the following results. LPS up-regulated mucin and cytokine mRNA expression and secretion in goblet cells in a concentration and time-dependent manner, with a maximum output at an LPS concentration of 100 ng/ml. LPS (100 ng/ml) increased mRNA expression of MUC5AC (2.4x), MUC5B (2.1x), and IL-8 (2.3x) and stimulated secretion of mucins (MUC5AC up to 39%, MUC5B up to 31%) and the inflammatory cytokine IL-8 (up to 10x). A significant correlation was found between the LPS-induced IL-8 secretion and secretion of mucins. These results suggest: (1) goblet cells, responding to the direct stimulation of bacterial LPS by two inflammatory-related processes such as production and secretion of the gel-forming mucins and the inflammatory cytokine IL-8, can be considered as an important part of mucosal immunity and (2) LPS- induced goblet cell mucin secretion can occur partly via IL-8-dependent pathway. 相似文献
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An intimate interplay exists between the bone and the immune system, which has been recently termed osteoimmunology. The activity
of immune cells affects the intrinsic balance of bone mineralization and resorption carried out by the opposing actions of
osteoblasts and osteoclasts. The aim of this study was to determine the possible interaction between inflammatory-induced
conditions and matrix metalloproteinases-2,-9 (MMP-2,-9) synthesis and secretion by bone marrow-derived osteoprogenitor cells
during advanced stages of osteogenesis. Rat bone marrow-derived mesenchymal stem cells (MSCs) were cultured in the presence
of osteogenic supplements in order to direct the cells towards the osteogenic differentiation lineage. At the late stages
of osteogenesis, assessed by histochemistry, immunohistochemistry and RT-PCR, cultures were exposed to pro-inflammatory cytokines,
tumor necrosis factor-alpha (TNF-α) and interleukin-1alpha (IL-1α). Biochemical, histochemical and molecular biology techniques
were used to discern the influence of pro-inflammatory cytokines on MMP-2,-9 synthesis and secretion. Results indicated that
MMP-9 synthesis and secretion were significantly induced after exposure to the cytokines (TNF-α, IL-1α) treatment, while MMP-2
levels remained unchanged. These results indicate that in response to inflammatory processes, osteoblasts, in addition to
osteoclasts, can also be involved and contribute to the process of active bone resorption by secretion and activation of MMPs. 相似文献
9.
Alagappan VK McKay S Widyastuti A Garrelds IM Bogers AJ Hoogsteden HC Hirst SJ Sharma HS 《Cell biochemistry and biophysics》2005,43(1):119-129
Airflow obstruction in chronic airway disease is associated with airway and pulmonary vascular remodeling, of which the molecular
mechanisms are poorly understood. Paracrine actions of angiogenic factors released by resident or infiltrating inflammatory
cells following activation by proinflammatory cytokines in diseased airways could play a major role in the airway vascular
remodeling process. Here, the proinflammatory cytokines interleukin (IL)-1β, and tumor necrosis factor (TNF)-α were investigated
on cell cultures of human airway smooth muscle (ASM) for their effects on mRNA induction and protein release of the angiogenic
peptide, vascular endothelial growth factor (VEGF). IL-1β (0.5 ng/mL) and TNF-α (10ng/mL) each increased VEGF mRNA (3.9 and
1.7 kb) expression in human ASM cells, reaching maximal levels between 16 and 24 and 4 and 8h, respectively. Both cytokines
also induced a time-dependent release of VEGF, which was not associated with increased ASM growth. Preincubation of cells
with 1μM dexamethasone abolished enhanced release of VEGF by TNF-α. The data suggest that human ASM cells express and secrete
VEGF in response to proinflammatory cytokines and may participate in paracrine inflammatory mechanisms of vascular remodeling
in chronic airway disease. 相似文献
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Johanna Westra Berber Doornbos-van der Meer Peter de Boer Miek A van Leeuwen Martin H van Rijswijk Pieter C Limburg 《Arthritis research & therapy》2004,6(4):R384
In inflammatory processes, the p38 mitogen-activated protein kinase (MAPK) signal transduction route regulates production
and expression of cytokines and other inflammatory mediators. Tumor necrosis factor α (TNF-α) is a pivotal cytokine in rheumatoid
arthritis and its production in macrophages is under control of the p38 MAPK route. Inhibition of the p38 MAPK route may inhibit
production not only of TNF-α, but also of other inflammatory mediators produced by macrophages, and indirectly of inflammatory
mediators by other cells induced by TNF-α stimulation. Here we investigate the effects of RWJ 67657, a p38 MAPK inhibitor,
on mRNA expression and protein production of TNF-α and other inflammatory mediators, in monocyte-derived macrophages. A strong
inhibition of TNF-α was seen at pharmacologically relevant concentrations of RWJ 67657, but also inhibition of mRNA expression
of IL-1β, IL-8, and cyclooxygenase-2 was shown. Furthermore, it was shown that monocyte-derived macrophages have a high constitutive
production of matrix metalloproteinase 9, which is not affected by p38 MAPK inhibition. The results presented here may have
important implications for the treatment of rheumatoid arthritis. 相似文献
12.
Campo GM Avenoso A Campo S Angela D Ferlazzo AM Calatroni A 《Molecular and cellular biochemistry》2006,292(1-2):169-178
Several reports have shown that a number of cytokines such as tumor necrosis-α (TNF-α), interferon-γ (IFN-γ), and interleukin-β (IL-1β) are capable to induce hyaluronan sinthases (HASs) mRNA expression in different cell culture types. The obvious consequence of this stimulation is a marked increment in hyaluronan (HA) production. It has been also reported that oxidative stress, by itself, may increase HA levels. The aim of this study was to evaluate how TNF-α, IFN-γ,IL−1β, and exposition to oxidative stress may modulate HAS activities in normal human skin fibroblasts. Moreover, the effects on HAS mRNA expression of the concomitant treatment with cytokines and oxidants, and the HA concentrations after treatments, were studied. TNF-α, IFN-γ, and IL-1β were added to normal or/and exposed to FeSO4 plus ascorbate fibroblast cultures and HAS1, HAS2 and HAS3 mRNA content, by PCR-real time, was assayed 3,h later. HA levels were also evaluated after 24,h incubation. The treatment of fibroblasts with cytokines up-regulated HASs gene expression and increased HA production. IL-1β induced HAS mRNA expression and HA production more efficiently than TNF-α and IFN-γ. The exposition of the fibroblasts with the oxidant system markedly increased HAS activities while slightly HA production. The concomitant treatment of cells with the cytokines and the oxidant was able to further enhance, in a dose dependent way, with synergistic effect on HAS mRNA expression. On the contrary HA levels resulted unaffected by the concomitant treatment, and resemble those obtained with the exposure to FeSO4 plus ascorbate only. This lack in HA production could be due to the deleterious action of free radicals on the HA synthesis. 相似文献
13.
In diabetes the endothelium is either chronically or transiently exposed to hyperglycemic conditions. In addition, endothelial
dysfunction in diabetes is related to changes in the inflammatory response and the turnover of extracellular matrix. This
study was undertaken to study the effects of inflammatory stimuli on one particular matrix component, the heparan sulfate
(HS) proteoglycans (PGs) synthesized by primary human umbilical cord vein endothelial cells (HUVEC). Such cells were cultured
in vitro in 5 mM and 25 mM glucose. The latter concentration was used to mimic hyperglycemic conditions in short-term experiments.
HUVEC were also cultured in the presence of the inflammatory agents tumor necrosis factor α (TNF-α), interleukin 1α (IL-1α),
interleukin 1β (IL-1β) and transforming growth factor β (TGF-β). The cells were labeled with 35S-sulfate and 35S-PGs were recovered for further analyses. The major part of the 35S-PGs was secreted to the medium, irrespective of type of stimuli. Secreted 35S-PGs were therefore isolated and subjected to further analyses. TNF-α and IL-1α slightly increased the release of 35S-PGs to the culture medium, whereas IL-1β treatment gave a significant increase. The different treatments neither changed
the ratio of 35S-HS and 35S-chondroitin sulfate (CS) nor the macromolecular properties of the 35S-PGs. However, the 35S-HS chains were slightly increased in size after TNF-α treatment, and slightly decreased after TGF-β treatment, but not affected
by the other treatments. Compositional analysis of labeled disaccharides showed changes in the amount of 6-O-sulfated glucosamine residues after treatment with TNF-α, IL-1α and IL-1β. Western immunoblotting showed that major HSPGs
recovered from these cells were collagen XVIII, perlecan and agrin, and that secretion of these distinct PGs was increased
after IL-1β stimulation. Hence, short term inflammatory stimuli increased the release of HSPGs in HUVEC and affected both
the size and sulfation pattern of HS, depending on type of stimuli. 相似文献
14.
A thorough understanding of the immune system, including the role of different cytokines, during inflammatory diseases in
ruminants could lead to the development of new diagnostic methods and treatments. Tumour necrosis factor-α (TNF-α) is an important
cytokine in the onset of the inflammatory responses. Unfortunately, the number of studies on cytokines, like TNF-α, in ruminants
is limited due to a lack of species-specific reagents. As cytokines have remained rather conserved during evolution, cross-reactivity
between animal species may occur. Therefore, the aim of the present study was to investigate 5 commercially available antibodies
against human TNF-α for their ability to cross-react with ovine and/or bovine TNF-α, using a bead-based flow cytometric method.
Two of the antibody clones (Mab 11 and 6401.1111) showed cross reactivity with ovine recombinant TNF-α in concentrations above
2.5 ng/ml. However, none of the antibodies detected TNF-α in bovine milk, or serum containing known concentrations of bovine
TNF-α, as earlier determined with ELISA. The results could be due to inability of the antibodies to cross-react between species,
but quenching of the signal by matrix proteins might also have lowered the response. 相似文献
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Preciado-Patt Liana Cahalon Liora Hershkovitz Rami Lider Ofer Pras Mordechai Fridkin Mati 《International journal of peptide research and therapeutics》1998,5(5-6):349-355
Summary Serum amyloid A (SAA), an acute-phase reactant, exists naturally as a minor protein in the sera of healthy individuals. However,
its levels in sera are increased markedly during various transient and chronic inflammatory diseases, often concomitantly
with accumulation at inflicted sites. SAA is synthesized mainly in the liver following the synergistic action of cytokines,
mainly tumor necrosis factor-α (TNF-α) and interleukin-1 and-6 (IL-1 and IL-6). It was already shown by us that upon interaction
with SAA or amyloid A (AA), the extracellular matrix (ECM) and laminin induced the adhesion of resting human CD4+ T-cells in an apparently β1-integrin-mediated manner. Herein we have shown that the SAA-ECM complex modulates the regulation of cytokine synthesis by
human T-lymphocytes. The SAA-ECM complex dramatically enhanced the release of TNF-α by human T-cells in a dose-dependent manner,
reaching its maximal effect in the presence of 100 μM recombinant SAA. The SAA domain, responsible for the enhanced release
of TNF-α by human T-lymphocytes, is apparently the amyloid A protein (AA, i.e. SAA2-82). Specifically, TNF-α enhanced secretion
is mediated through intimate interactions of SAA/AA, with laminin. Thus, the ECM serving as a temporary anchorage site for
SAA and AA seems to be involved in regulating TNF-α secretion and the recruitment and accumulation of immunocytes in extravascular,
inflammatory compartments. 相似文献
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Uz YH Murk W Bozkurt I Kizilay G Arici A Kayisli UA 《Histochemistry and cell biology》2011,135(1):83-91
Endometriosis is a common inflammatory gynecological disease characterized by the presence of endometrial tissue outside of
the uterine cavity. The c-Jun N-terminal kinase (JNK) is a subfamily of the mitogen-activated protein kinases (MAPKs) involved
in cellular processes ranging from cytokine expression to apoptosis, and is activated in response to inflammation and cellular
stress. We hypothesized that inflammatory cytokines in the peritoneal microenvironment increase JNK MAPK activity in endometriotic
endothelial cells, and that human endometrial endothelial cells (HEECs) may be involved in inflammatory pathogenesis of endometriosis.
Thus, we evaluated the expression of the total- and phosphorylated-(phospho)-JNK in endometrial and endometriotic endothelial
cells in vivo, and in HEECs treated with normal peritoneal fluid (NPF), endometriotic peritoneal fluid (EPF), and the inflammatory cytokines
interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in vitro. Phospho-JNK immunoreactivity in HEECs in normal
endometrium was significantly higher in the early proliferative and late secretory phases compared to other phases. Both eutopic
and ectopic HEECs from the early secretory phase also revealed higher phospho-JNK immunoreactivity, compared to their respective
cycle-matched normal HEECs. Moreover, HEECs treated with EPF showed significantly higher phospho-JNK levels compared to that
in HEECs treated with NPF. In conclusion, our in vivo and in vitro findings suggest that increased phosphorylation of JNK
in HEECs from women with endometriosis is likely due to high level of IL-1β and TNF-α in peritoneal fluid; this in turn may
up-regulate inflammatory cytokine expression and thus play a role in the pathogenesis of endometriosis. 相似文献
19.
β-1,4-galactosyltransferase I (β-1,4-GalT I) plays an important role in the synthesis of the backbone structure of adhesion molecules involved in leukocyte–endothelial
cell interaction. The expression of β-1,4-GalT I mRNA increased in primary human endothelial cells after exposure to tumor necrosis factor-α (TNF-α). In the central nervous system (CNS), astrocytes play a pivotal role in immunity as immunocompetent cells by secreting
cytokines and inflammatory mediators, there are two types of astrocytes. Type-1 astrocytes can secrete TNF-α when stimulated
with Lipopolysaccharide (LPS), while the responses of type-2 astrocytes during inflammation are unknown. So we examined the
expression change of β-1,4-GalT I mRNA in type-2 astrocytes after exposure to TNF-α and LPS. Real-time PCR showed that TNF-α or LPS affected β-1,4-GalT I mRNA expression in a time- and dose-dependent manner. RT-PCR analysis revealed that TNFR1 and TNFR2 were present
in normal untreated type-2 astrocytes, and that TNF-α, TNFR1 and TNFR2 increased in type-2 astrocytes after exposure to TNF-α or LPS. Immunocytochemistry showed that TNFR1 was
expressed in the cytoplasm, nucleus and processes of normal untreated type-2 astrocytes, and distributed mainly in the cytoplasm
and processes after exposure to LPS. TNFR2 was mainly expressed in the nucleus of normal untreated type-2 astrocytes, and
distributed mainly in the processes of type-2 astrocytes after exposure to LPS. Both anti-TNFR1 and anti-TNFR2 antibodies
suppressed β-1,4-GalT I mRNA expression induced by TNF-α or LPS. From these results, we conclude that TNF-α signaling via both TNFR1 and TNFR2 translocated from nucleus to cytoplasm or processes is sufficient to induce β-1,4-GalT I mRNA. In addition, we observed that not only exogenous TNF-α but also TNF-α produced by type-2 astrocytes affected β-1,4-GalT I mRNA production in type-2 astrocytes. These results suggest that an autocrine loop involving TNF-α contributes
to the production of β-1,4-GalT I mRNA in response to inflammation.
Chunlin Xia is the co-first author. 相似文献
20.
Ethyl acetate extracts of alfalfa (Medicago sativa L.) sprouts inhibit lipopolysaccharide-induced inflammation in vitro and in vivo 总被引:1,自引:0,他引:1
Yong-Han Hong Wen-Wan Chao Miaw-Ling Chen Bi-Fong Lin 《Journal of biomedical science》2009,16(1):64-12
This study aimed to investigate if food components that exert anti-inflammatory effects may be used for inflammatory disorders
by examining alfalfa sprout ethyl acetate extract (ASEA). The cytokine profile and life span of BALB/c mice with acute inflammation
after intra-peritoneal (ip) injection of 15 mg/kg BW lipopolysaccharide (LPS) were determined. The results showed that the
life span of LPS-induced inflammatory mice were negatively correlated with serum levels of TNF-α, IL-6, and IL-1β at 9 hr
after LPS-injection, which indicated that suppressing these cytokines in the late phase of inflammation may be beneficial
for survival. The in vitro experiment then showed that ASEA significantly reduced IL-6 and IL-1β production and the NF-κB trans-activation activity
of mitogen-stimulated RAW264.7 cells. To further evaluate the anti-inflammatory effects of ASEA in vivo, BALB/c mice were tube-fed with 25 mg ASEA/kg BW/day in 50 μl sunflower oil, while the control and PDTC (pyrrolidine dithiocarbamate,
an anti-inflammatory agent) groups were tube-fed with 50 μl sunflower oil/day only. After one week of tube-feeding, the PDTC
group was injected with 50 mg/kg BW PDTC and one hour later, all of the mice were injected with 15 mg/kg BW LPS. The results
showed that the ASEA and PDTC groups had significantly lower serum TNF-α, IL-6, and IL-1β levels at 9 hr after LPS challenge,
and significantly higher survival rates than the control group. This study suggests that ASEA supplementation can suppress
the production of pro-inflammatory cytokines and alleviate acute inflammatory hazards. 相似文献