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1.
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
2.
Miki Watanabe Sulaiman Sheriff Theresa A. Ramelot Nijiati Kadeer Junho Cho Kenneth B. Lewis Ambikaipakan Balasubramaniam Michael A. Kennedy 《International journal of peptide research and therapeutics》2011,17(4):281-299
After severe burn injury, proinflammatory cytokine levels are elevated in serum and skeletal muscle, which in turn increases
protein breakdown and decreases protein synthesis. In this study, C2C12 mouse skeletal muscle cell line myotubes were exposed
to proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) as an in vitro cell-line model of catabolic
response to burn injury and then treated with des-acyl ghrelin (DAG), a 28 amino acid polypeptide hormone thought to inhibit
protein breakdown and increase protein synthesis, to assess its therapeutic potential. Nuclear magnetic resonance-based metabonomics
was used to monitor metabolic activity of C2C12 myotubes under four treatment conditions: (1) control, (2) TNF-α/IFN-γ (TI),
(3) DAG (DA), and (4) TNF-α/IFN-γ followed by DAG (TIDA) to assess the effect of DAG treatment on cellular metabolic response
during basal or catabolic conditions. Twelve metabolites showed significant changes in concentrations following treatments
in the hydrophilic cell extracts. Lactate (P < 10−4) and citrulline (P < 10−9) increased with TNF-α/IFN-γ treatment, indicating increased protein degradation, and returned to control levels in the TIDA
group. Adenosine nucleotide levels had decreased trends in TI myotubes that returned to baseline levels after DAG treatment
(P < 10−4). Guanidinoacetate and pantothenate, metabolites involved in protein synthesis and cell proliferation, had increased concentration
trends following DAG treatment in both the DA and TIDA groups. Our metabonomics analysis provides further evidence that DAG
counteracts the catabolic response caused by elevated muscle TNF-α/IFN-γ cytokine levels following severe burns and can play
a potential therapeutic role in treatment of burn injury. 相似文献
3.
The role of cytokines in the pathophysiology of amyotrophic lateral sclerosis (ALS) and its relation to clinical outcome has
not been clearly defined. We evaluated tumor necrosis factor-alpha (TNF-α), interferon-γ (IFN-γ) and nitric oxide (NO) levels
in the serum of 22 ALS patients and 20 controls. Serum TNF-α levels and IFN-γ levels were significantly (P < 0.001) elevated in ALS patients. We also observed NO levels to be significantly (P < 0.05) increased with respect to normal subjects. We further noticed positive correlation between the duration of ALS and
these proinflammatory molecule levels. Exitotoxicity and oxidative stress are known to play a crucial role in the neurodegeneration
observed in ALS. Since high levels of TNF-α are known to be cytotoxic, it could be that a complex interplay of these effectors
may be one of the factors underlying the progression of ALS. This study confirms the involvement of inflammation in ALS and
the need to develop surrogate markers to check the progression of this disease. 相似文献
4.
IL-10, IL-13, IFN-γ, tumor necrosis factor (TNF)-α, LT-α, CD154, and TNF-related activation-induced cytokine (TRANCE) were expressed by 2-20% of rheumatoid arthritis (RA) synovial tissue CD4+ memory T cells, whereas CD4+ cells that produced IL-2, IL-4, or IL-6 were not detected. Expression of none of these molecules by individual CD4+ cells correlated with the exception of TRANCE and IL-10, and TRANCE and TNF-α. A correlation between expression of IL-10 and CCR7, LT-α and CCR6, IFN-γ and CCR5, and TRANCE and CXCR4 was also detected. 相似文献
5.
A comparative study was done using J774A.1 and J774A. 1-derived transfected cells (J774A.1 C.1) containing antisense tumor
necrosis factor α (TNF-α) plasmid to determine the role of endogenous TNF-α on nitric oxide production as well as on the growth
ofMycobacterium microti in interferon γ (IFN-γ)- and lipopolysaccharide (LPS)-treated cells. On stimulation with IFN-γ and LPS a higher level of
NO was observed in J774A.1 cells compared to J774A.1 C.1 which indicated that endogenous TNF-α is required for the production
of NO. Comparing the effect of IFN-γ and LPS on the intracellular growth ofM. microti, the growth-reducing activity was higher in J774A.1 cells than in J774A.1 C.1 cells and was not completely abrogated in the
presence of the nitric oxide inhibitorN
G-methyl-l-arginine (l-NMA). J774A.1 C.1 cells infected withM. microti produced a significant amount of NO when exogenous TNF-α was added along with IFN-γ and LPS and the concentration of intracellular
bacteria decreased almost to that in IFN-γ and LPS treated parental J774A.1 cells. Addition of exogenous TNF-α even in the
presence ofl-NMA in J774.1 C.1 cells could also partially restore intracellular growth inhibition ofM. microti caused by IFN-γ and LPS. TNF-α is probably required for the production of NO in J774A.1 cells by IFN-γ and LPS but TNF-α
and NO are independently involved in the killing of intracellularM. microti with IFN-γ and LPS. 相似文献
6.
Daneshmandi S Pourfathollah AA Pourpak Z Heidarnazhad H Kalvanagh PA 《Molecular biology reports》2012,39(2):1845-1853
Asthma is a multifactor inflammatory disorder, and its management requires understanding of its various pathogenesis and control
mechanisms. Cytokines and other inflammatory mediators are important factors in asthma pathophysiology. In this study, we
evaluated the role of cytokine polymorphisms in the asthma susceptibility, progress, control, and lung functions. IL-4-C590T
polymorphism by PCR-RFLP method, IFN-γ T+874A, TNF-α-A308G, IL-6 G−174C and TGF-β T+869C variants by ARMS-PCR method and IgE
serum level by ELISA technique were determined in 81 asthmatic patients and 124 normal subjects. Asthma diagnosis, treatment
and control levels were considered using standard schemes and criteria. TNF-α−308GA genotype was more frequent in asthmatics
(P = 0.025, OR 3.352), and polymorphisms between different asthma control levels (P > 0.05) were not different. IFN-γ+874AT genotype had a positive correlation with the familial history of asthma (P = 0.034, OR 2.688). IL-6−174C allele (P = 0.045), TNF-α−308GG genotype (P = 0.002) and TNF-α−308G allele (P = 0.004) showed reduced values, and TNF-α−308GA genotype (P = 0.002) increased FEF25-75 value in asthmatics. IFN-γ+874AA genotype caused a decrease in FVC factor (P = 0.045). This study showed that TNF-α−308GA is a risk factor for asthma, but cytokine gene variants do not affect asthma
control and IgE serum levels. Variants producing lower levels of IL-6, TNF-α and IFN-γ are associated with reduced pulmonary
capacities. To achieve an appropriate schema for asthma management, further studies with consideration of different aspects
in a larger group of patients would be more elucidative. 相似文献
7.
Katarzyna Grzelkowska-Kowalczyk Wioletta Wieteska-Skrzeczyńska 《Cellular & molecular biology letters》2010,15(1):13-31
The aim of this study was to compare the effects of TNF-α, IL-1β and IFN-γ on the activation of protein kinase B (PKB), p70S6k, mitogen-activated protein kinase (MAPK) and p90
rsk
, and on IGF-I-stimulated glucose uptake and protein synthesis in mouse C2C12 myotubes. 100 nmol/l IGF-I stimulated glucose
uptake in C2C12 myotubes by 198.1% and 10 ng/ml TNF-α abolished this effect. Glucose uptake in cells differentiated in the
presence of 10 ng/ml IFN-γ increased by 167.2% but did not undergo significant further modification upon the addition of IGF-I.
IGF-I increased the rate of protein synthesis by 249.8%. Neither TNF-α nor IFN-γ influenced basal protein synthesis, but both
cytokines prevented the IGF-I effect. 10 ng/ml IL-1β did not modify either the basal or IGF-I-dependent glucose uptake and
protein synthesis. With the exception of TNF-α causing an 18% decrease in the level of PKB protein, the cellular levels of
PKB, p70S6k, p42MAPK, p44MAPK and p90
rsk
were not affected by the cytokines. IGF-I caused the phosphorylation of PKB (an approximate 8-fold increase above the basal
value after 40 min of IGF-I treatment), p42MAPK (a 2.81-fold increase after 50 min), and the activation of p70S6k and p90
rsk
, manifesting as gel mobility retardation. In cells differentiated in the presence of TNF-α or IFN-γ, this IGF-I-mediated
PKB and p70S6k phosphorylation was significantly diminished, and the increase in p42MAPK and p90
rsk
phosphorylation was prevented. The basal p42MAPK phosphorylation in C2C12 cells treated with IFN-γ was high and comparable with the activation of this kinase by IGF-I. Pretreatment
of myogenic cells with IL-1β did not modify the IGF-I-stimulated phosphorylation of PKB, p70S6k, p42MAPK and p90
rsk
. In conclusion: i) TNF-α and IFN-γ, but not IL-1β, if present in the extracellular environment during C2C12 myoblast differentiation,
prevent the stimulatory action of IGF-I on protein synthesis. ii) TNF-α- and IFN-γ-induced IGF-I resistance of protein synthesis
could be associated with the decreased phosphorylation of PKB and p70S6k. iii) The activation of glucose uptake in C2C12 myogenic cells treated with IFN-γ is PKB independent. iv) The similar effects
of TNF-α and IFN-γ on the signalling and action of IGF-I on protein synthesis in myogenic cells could suggest the involvement
of both of these cytokines in protein loss in skeletal muscle. 相似文献
8.
Tae-Young Lee Yang-Hyun Kim Sun-Woo Yoon Jai-Chul Choi Jai-Myung Yang Chul-Joong Kim John T. Schiller Moon-Hee Sung Haryoung Poo 《Cancer immunology, immunotherapy : CII》2009,58(11):1781-1794
Previously, we reported that the oral administration of high molecular mass poly-γ-glutamate (γ-PGA) induced antitumor immunity
but the mechanism underlying this antitumor activity was not understood. In the present study, we found that application of
high molecular mass γ-PGA induced secretion of tumor necrosis factor (TNF)-α from the bone-marrow-derived macrophages of wild
type (C57BL/6 and C3H/HeN) and Toll-like receptor 2 knockout (TLR2−/−) mice, but not those of myeloid differentiation factor 88 knockout (MyD88−/−) and TLR4-defective mice (C3H/HeJ). Production of interferon (IFN)-γ-inducible protein 10 (IP-10) in response to treatment
with γ-PGA was almost abolished in C3H/HeJ mice. In contrast to LPS, γ-PGA induced productions of TNF-α and IP-10 could not
be blocked by polymyxin B. Furthermore, γ-PGA-induced interleukin-12 production was also impaired in immature dendritic cells
(iDCs) from MyD88−/− and C3H/HeJ mice. Downregulation of MyD88 and TLR4 expression using small interfering RNA (siRNA) significantly inhibited
γ-PGA-induced TNF-α secretion from the RAW264.7 cells. γ-PGA-mediated intracellular signaling was markedly inhibited in C3H/HeJ
cells. The antitumor effect of γ-PGA was completely abrogated in C3H/HeJ mice compared with control mice (C3H/HeN) but significant
antitumor effect was generated by the intratumoral administration of C3H/HeN mice-derived iDCs followed by 2,000 kDa γ-PGA
in C3H/HeJ. These findings strongly suggest that the antitumor activity of γ-PGA is mediated by TLR4.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
9.
Bert De Klerck Isabelle Carpentier Rik J Lories Yvette Habraken Jacques Piette Geert Carmeliet Rudi Beyaert Alfons Billiau Patrick Matthys 《Arthritis research & therapy》2004,6(3):R220
Collagen-induced arthritis (CIA) in mice is accompanied by splenomegaly due to the selective expansion of immature CD11b+ myeloblasts. Both disease manifestations are more pronounced in interferon-γ receptor knock-out (IFN-γR KO) mice. We have
taken advantage of this difference to test the hypothesis that the expanding CD11b+ splenic cell population constitutes a source from which osteoclast precursors are recruited to the joint synovia. We found
larger numbers of osteoclasts and more severe bone destruction in joints of IFN-γR KO mice than in joints of wild-type mice.
Osteoclast-like multinucleated cells appeared in splenocyte cultures established in the presence of macrophage colony-stimulating
factor (M-CSF) and stimulated with the osteoclast-differentiating factor receptor activator of NF-κB ligand (RANKL) or with
tumour necrosis factor-α (TNF-α). Significantly larger numbers of such cells could be generated from splenocytes of IFN-γR
KO mice than from those of wild-type mice. This was not accompanied, as might have been expected, by increased concentrations
of the intracellular adaptor protein TRAF6, known to be involved in signalling of RANKL- and TNF-α-induced osteoclast formation.
Splenocyte cultures of IFN-γR KO mice also produced more TNF-α and more RANKL than those of wild-type mice. Finally, splenocytes
isolated from immunised IFN-γR KO mice contained comparatively low levels of pro-interleukin-1β (pro-IL-1β) and pro-caspase-1,
indicating more extensive conversion of pro-IL-1β into secreted active IL-1β. These observations provide evidence that all
conditions are fulfilled for the expanding CD11b+ splenocytes to act as a source of osteoclasts and to be indirectly responsible for bone destruction in CIA. They also provide
a plausible explanation for the higher susceptibility of IFN-γR KO mice to CIA. 相似文献
10.
The mechanism by which lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA) induces production of proinflammatory
cytokines in murine macrophages, and the role of phosphatidylinositol 3-kinase (PI3-kinase) have not been well investigated.
Activation of nuclear factor κB (NF-κB) is initiated by the phosphorylation of the inhibitory subunit, IκB, which targets
IκB for degradation and leads to the release of active NF-κB. In this study we demonstrate that 2- (4-morpholinyl)-8-phenylchromone
(LY294002), which inhibits PI3-kinase, specifically inhibited degradation of IκBα in RAW264.7 cells stimulated with interferon-γ
(IFN-γ) plus LPS or IFN-γ plus PMA. To elucidate the importance of this activity in RAW264.7 cells, we examined tumor necrosis
factor-α (TNF-α) and interleukin IL)-6 production in the activated cells. Pretreatment of the cells with LY294002 resulted
in the inhibition of TNF-α and IL-6 production in RAW264.7 cells stimulated with IFN-γ plus LPS or IFN-γ plus PMA. Furthermore,
LY294002 inhibited the production of nitric oxide NO) in RAW264.7 cells stimulated with IFN-γ plus LPS or IFN-γ plus PMA.
LY294002 also inhibited inducible NO synthase (iNOS) mRNA expression in the activated RAW264.7 cells. In conclusion, the present
results suggest that PI3-kinase is involved in the signal transduction pathway responsible for LPS- or PMA-mediated TNF-α
and IL-6 production, and that LY294002 inhibits NO generation through blocking the degradation of IκBα in activated RAW264.7
cells.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
11.
Sandy Pelletier Simon Tanguay Stephen Lee Lakshman Gunaratnam Nathalie Arbour Réjean Lapointe 《Cancer immunology, immunotherapy : CII》2009,58(8):1207-1218
Objectives Patients with renal cell carcinomas (RCC) have few treatment options, underscoring the importance of developing new approaches
such as immunotherapy. However, few tumor associated antigens (TAA), which can be targeted by immunotherapy, have been identified
for this type of cancer. von Hippel-Lindau clear cell RCC (VHL−/−RCC) are characterized by mutations in the VHL tumor suppressor gene. Loss of VHL function causes the overexpression of transforming
growth factor (TGF)-α, leading us to hypothesize that TGF-α could be a potential TAA for immunotherapy of kidney cancer, which
was evaluated in this study.
Methods and results We first confirmed the absent or weak expression of TGF-α in important normal tissues as well as its overexpression in 61%
of renal tumors in comparison to autologous normal kidney tissues. In addition, we demonstrated the immunogenicity of TGF-α,
by expanding many T cell lines specific for certain TGF-α peptides or the mature TGF-α protein, when presented by major histocompatibility
complex (MHC) molecules on the surface of antigen-presenting cells. Interestingly, some of these TGF-α-specific T cells were
polyfunctionals and secreted IFN-γ, TNF-α and IL-2.
Conclusion We have shown that TGF-α is a valid candidate TAA, which should allow the development of a targeted immunotherapy. 相似文献
12.
Farshad Malihi Azadeh Hosseini-Tabatabaei Hadi Esmaily Reza Khorasani Maryam Baeeri Mohammad Abdollahi 《Central European Journal of Biology》2009,4(3):369-380
Type 1 diabetes mellitus (T1DM) is characterized by an impairment of the insulin-secreting beta cells with an immunologic
base. Inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and free radicals are believed
to play key roles in destruction of pancreatic β cells. The present study was designed to investigate the effect of Silybum marianum seed extract (silymarin), a combination of several flavonolignans with immunomodulatory, anti-oxidant, and anti-inflammatory
potential on streptozotocin (STZ)-induced T1DM in mouse. Experimental T1DM was induced in male albino mice by IV injection
of multiplelow- doses of STZ for 5 days. Seventy-two male mice in separate groups received various doses of silymarin (20,
40, and 80 mg/kg) concomitant or after induction of diabetes for 21 days. Blood glucose and pancreatic biomarkers of inflammation
and toxic stress (IL-1β, TNF-α, myeloperoxidase, lipid peroxidation, protein oxidation, thiol molecules, and total antioxidant
capacity) were determined. Silymarin treatment reduced levels of inflammatory cytokines such as TNF-α and IL-1β and oxidative
stress mediators like myeloperoxidase activity, lipid peroxidation, carbonyl and thiol content of pancreatic tissue in an
almost dose dependent manner. No marked difference between the prevention of T1DM and the reversion of this disease by silymarin
was found. Use of silymarin seems to be helpful in T1DM when used as pretreatment or treatment. Benefit of silymarin in human
T1DM remains to be elucidated by clinical trials. 相似文献
13.
Miao Yin Liang Zhang Xiao-ming Sun Liu-feng Mao Jie Pan 《Molecular biology reports》2010,37(4):2049-2054
To investigate the effect of apolipoprotein E (apoE) on cytokine expression profile of the liver of young mice, quantitative
RT-PCR (qRT-PCR) assay and cytokine antibody array for multiplex analysis of 62 cytokines have been used to analyze characteristics
of expression of cytokines in the liver of 6-week-old apoE-null (apoE−/−) mice. The levels of plasma cytokines were also analyzed. The mRNA level of IL-1β, IL-2, IL-6, ICAM-1, VCAM-1, MCP-1, NF-κB
(p65), IFN-γ and IκB-α were increased significantly in apoE−/− mice comparative to wild-type (WT) mice. IL-4, IL-10 and GM-CSF, however, were slightly decreased. Compared with WT, levels
of 21 cytokines altered twofold or more in apoE−/− mice, including 10 cytokines increased and 11 decreased. Expression patterns of IL-1β, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-γ
and VCAM-1 showed identical trend between cytokine antibody array and qRT-PCR analysis. Moreover, levels of IL-1β, IFN-γ and
IL-6 in the plasma were elevated, while IL-4 was lightly decreased in apoE−/− mice compared to those in WT mice. These results implied that promotion of type I immune response in the liver of young apoE−/− mice due to alteration of these cytokines, and the phenotypes may be caused by the regulation of NF-κB. The inflammation
and lipid metabolism dysfunction in the liver cooperated in dysfunction of the liver in young apoE−/− mice. 相似文献
14.
R. K. Saxena Q. B. Saxena T. L. Whiteside R. H. Goldfarb R. B. Herberman 《Journal of biosciences》1996,21(1):13-25
A cytokine which augments the expression of major histocompatibility complex (MHC) I antigens on K562 and gastric carcinoma
tumour (HR) cells, has been isolated from the culture supernatant of Concanavalin-A (Con-A) activated human peripheral blood
mononuclear cells. The factor, termed MHC augmenting factor (MHC- AF) has been partially purified by Sephadex G- 100 column
chromatography, preparative isoelectric focusing and HPLC with ion- exchange as well as sizing columns. MHC-AF activity is
associated with a 35 kDa molecule which has pI of 6.0. Interferon (IFN)-α, \, tumour necrosis factor (TNF), Interleukin (IL)-2,
IL-4, IL-5 and IL-7 had no significant effect in MHC- AF bioassay, but IFN-γ had significant MHC-AF activity. Antibodies to
IFN-α, IFN-\ and TNF-α did not block the activity of MHC-AF, but anti-IFN-y antibodies could partially neutralize the activity.
However, unlike IFN-γ, MHC-AF activity was resistant to pH 2.0 treatment. Purified MHC-AF preparations did not have any activity
in WISH cell/encephalo myocarditis virus (EMC) IFN bioassays. In addition, anti-IFN-y affinity column did not retain MHC-AF
activity. These results indicate that a MHC-AF distinct from IFN-γ, is produced by activated human mononuclear cells. 相似文献
15.
Rongrong Hou Jing Zhang Tao Yin Hongwei Cao Nanyan Zhang Xiaomiao Li Li Wang Ying Xing Deqiang Li Qiuhe Ji 《Apoptosis : an international journal on programmed cell death》2010,15(8):877-886
Phosphatase and tensin homolog (PTEN), a tumor suppressor gene, by negatively regulating the PI3K-Akt signaling pathway, participates
in multiple biological processes such as cell proliferation, apoptosis, differentiation, and migration. Recent studies show
that selective deletion of PTEN in pancreatic β-cells leads to resistance to streptozotocin (STZ)-induced diabetes, but the
mechanism is unclear. One major mechanism underlying STZ toxicity is cytokine-mediated β-cell destruction in which oxidative
stress plays a key role. The present study investigated the role of PTEN in cytokine-induced β-cell apoptosis, and further
explored whether oxidative stress, particularly peroxynitrite formation, could regulate PTEN-Akt pathway. Incubation of βTC-6
cells with cytokine mixture (IL-1β, TNF-α, and IFN-γ) or exogenous peroxynitrite significantly increased apoptotic cell percentage,
elevated PTEN and p-PTEN levels, and inhibited Akt activation. Transfection with PTEN-specific siRNA protected βTC-6 cells
from cytokine or peroxynitrite-mediated cell apoptosis and partially reversed Akt inhibition. Furthermore, nitrotyrosine formation,
an indicator of peroxynitrite production, was significantly elevated after cytokine treatment. Preventing peroxynitrite formation
by administrating NAC/l-NMMA, or scavenging peroxynitrite directly by UA, attenuated cytokine-induced PTEN upregulation, Akt inhibition, and β-cell
apoptosis. These findings suggest that peroxynitrite-mediated PTEN upregulation plays an important role in cytokine-induced
pancreatic β-cell apoptosis. 相似文献
16.
THR0921 is a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist with potent anti-diabetic properties.
Because of the proposed role of PPARγ in inflammation, we investigated the potential of orally active THR0921 to inhibit the
pathogenesis of collagen-induced arthritis (CIA). CIA was induced in DBA/1J mice by the injection of bovine type II collagen
in complete Freund's adjuvant on days 0 and 21. Mice were treated with THR0921 (50 mg/kg/day) starting on the day of the booster
injection and throughout the remaining study period. Both clinical disease activity scores as well as histological scores
of joint destruction were significantly reduced in mice treated with THR0921 compared to untreated mice. Proliferation of
isolated spleen cells, as well as circulating levels of IgG antibody to type II collagen, was decreased by THR0921. Moreover,
spleen cell production of IFN-γ, tumor necrosis factor (TNF)-α and IL-1β in response to exposure to lipopolysaccharide or
type II collagen was reduced by in vivo treatment with THR0921. Steady state mRNA levels of TNF-α, IL-1β, monocyte chemotactic protein-1 and receptor activator of
nuclear factor κB ligand (RANKL) in isolated joints were all decreased in mice treated with THR0921. Finally, THR0921 inhibited
osteoclast differentiation of bone marrow-derived cells stimulated with macrophage colony-stimulating factor and RANKL. In
conclusion, THR0921 attenuates collagen-induced arthritis in part by reducing the immune response. As such, PPARγ may be an
important therapeutic target for rheumatoid arthritis. 相似文献
17.
Wujiang Liu Michael A. O’Donnell Xiaohong Chen Ruifa Han Yi Luo 《Cancer immunology, immunotherapy : CII》2009,58(10):1647-1655
Purpose The proper induction of cellular immunity is required for effective bacillus Calmette-Guérin (BCG) immunotherapy of bladder
cancer. It has been known that BCG stimulation of human peripheral blood mononuclear cells (PBMC) leads to the generation
of effector cells cytotoxic to bladder cancer cells in vitro. To improve BCG therapy, we previously developed human interferon
(IFN)-α 2B secreting recombinant (r) BCG (rBCG-IFN-α). We demonstrated that rBCG-IFN-α augmented T helper type 1 (Th1) cytokine
IFN-γ production by PBMC. In this study, we further investigated whether rBCG-IFN-α could also enhance PBMC cytotoxicity toward
bladder cancer cells.
Materials and methods PBMC were prepared from healthy individuals, left alone or stimulated with rBCG-IFN-α or control MV261 BCG, and used as effector
cells in 51Cr-release assays. Human bladder cancer cell lines T24, J82, 5637, TCCSUP, and UMUC-3 were used as target cells. To determine
the role of secreted rIFN-α as well as endogenously expressed IFN-γ and IL-2 in inducing the cytotoxicity, PBMC were stimulated
with rBCG-IFN-α in the presence of neutralizing antibodies to IFN-α, IFN-γ or IL-2. To determine the role of natural killer
(NK) and CD8+ T cells in inducing the cytotoxicity, both cell types were isolated after BCG stimulation of PBMC and used as effector cells
in 51Cr-release assays.
Results Non-stimulated PBMC showed basal levels of cytotoxicity against all target cell lines tested. MV261 BCG increased the PBMC
cytotoxicity by 1.8- to 4.2-fold. rBCG-IFN-α further increased the PBMC cytotoxicity by up to 2-fold. Elevated production
of IFN-γ and IL-2 by PBMC was observed after rBCG-IFN-α stimulation. Blockage of IFN-α, IFN-γ or IL-2 by neutralizing antibodies
during rBCG-IFN-α stimulation reduced or abolished the induction of PBMC cytotoxicity. Both NK and CD8+ T cells were found to be responsible for the enhanced PBMC cytotoxicity induced by rBCG-IFN-α with the former cell type being
more predominant.
Conclusions rBCG-IFN-α is an improved BCG agent that induces enhanced PBMC cytotoxicity against bladder cancer cells in vitro. This rBCG
strain may serve as an alternative to BCG for the treatment of superficial bladder cancer. 相似文献
18.
Wu L Zhao L Zheng Q Shang F Wang X Wang L Lang B 《Molecular and cellular biochemistry》2006,284(1-2):65-71
Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes guanosine or adenosine mononucleotide-dependent reversible conversion of oxaloacetate (OAA) and phosphoenolpyruvate (PEP). Mycobacterium (M) tuberculosis possesses a putative GTP-dependent PEPCK. To analyze the immune responses caused by PEPCK, the effects of PEPCK on the induction of CD4+ T cells and cytokines such as IFN-γ, IL-12 and TNF-α were evaluated in mice. It was found that the number of CD4+ T cells was increased in the PEPCK immunized mice although the change of the number of CD8+ T cells was not significant. The cytokines IFN-γ, IL-12 and TNF-α were increased significantly in the mice immunized with PEPCK than those of incomplete adjuvant. These characteristics were further demonstrated in the mice infected by pckA mutated BCG strain. The results indicate that PEPCK can effectively induce cell-mediated immune response by increasing activity of cytokines and PEPCK may be a promising new subunit vaccine candidate for tuberculosis. 相似文献
19.
Yanfeng Tuo Lanwei Zhang Xue Han Ming Du Yingchun Zhang Huaxi Yi Weiqin Zhang Yuehua Jiao 《World journal of microbiology & biotechnology》2011,27(3):505-511
The objective of this study was to evaluate the in vitro immunomodulating capacity of Lactobacillus
coryniformis subsp torquens T3L (L.
coryniformis T3L) isolated from traditional fermented yak’s milk in Tibet, China, and Lactobacillus paracasei supsp. paracasei M5L (L. paracasei M5L)isolated from kumiss in Sinkiang, China was used as control. The effects of live bacteria, cell wall and genomic DNA
of the two Lactobacillus strains on human peripheral blood mononuclear cells (PBMCs) proliferation, production of interleukin-12 (IL-12 p70), interferon
gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), and natural killer (NK) cell activity were assessed. The live bacteria,
cell wall and genomic DNA of the two lactobacilli exerted proliferative effects on PBMCs. Live bacteria at 1 × 106 c.f.u. ml−1, cell wall at 20 μg protein ml−1 and DNA at 50 μg DNA ml−1 of the strainS induced the secretion of IL-12 (p70), IFN-γ and TNF-α by PBMCs. NK cell activities increased after cultivation
of PBMCs with live bacteria, cell wall and DNA of the strains. Overall, these results demonstrate that the live bacteria,
cell wall and genomic DNA of the two Lactobacillus strains exhibit immunomodulating activity. 相似文献
20.
There is increasing interest in the generation of dendritic cells (DC) for cancer immunotherapy. In order to utilize DC in
clinical trials it is necessary to have standardized, reproducible and easy to use protocols. We describe here the process
development for the generation of DC as the result of investigation of culture conditions as well as consumption rates of
medium and cytokines. Our studies demonstrate that highly viable DC (93 ± 2%) can be produced from CD14+ enriched monocytes via immunomagnetic beads in a high yield (31 ± 6%) with X-VIVO 15, 400 U ml−1 GM-CSF and 2000 U ml−1 IL-4 without serum and feeding. For the maturation of DC different cocktails (TNF-α, IL-1β, IL-6, PGE2 and TNF-α, PGE2) were compared. In both cases cells expressed typical surface molecules of mature DC and induced high proliferative responses
in mixed lymphocyte reactions which led to IFN-γ producing T-lymphocytes. The data suggest that the use of this optimized,
easy to use protocol results in highly mature DC.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献