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1.
Neuroinflammation is a complex response to brain injury involving the activation of glia, release of inflammatory mediators
within the brain, and recruitment of peripheral immune cells. Interestingly, memory deficits have been observed following
many inflammatory states including infection, traumatic brain injury (TBI), normal aging, and Alzheimer’s disease (AD). Prostaglandins
(PGs), a class of lipid mediators which can have inflammatory actions, are upregulated by these inflammatory challenges and
can impair memory. In this paper, we critically review the success of nonsteroidal anti-inflammatory drugs, which prevent
the formation of PGs, in preventing neuroinflammation-induced memory deficits following lipopolysaccharide injection, TBI,
aging, and experimental models of AD in rodents and propose a mechanism by which PGs could disrupt memory formation. 相似文献
2.
Takata F Dohgu S Yamauchi A Sumi N Nakagawa S Naito M Tsuruo T Shuto H Kataoka Y 《Cellular and molecular neurobiology》2007,27(3):317-328
1. The present study was designed to clarify whether brain pericytes and pericyte-derived transforming growth factor-β1 (TGF-β1)
participate in cyclosporin A (CsA)-induced dysfunction of the blood-brain barrier (BBB).
2. The presence of brain pericytes markedly aggravated CsA-increased permeability of MBEC4 cells to sodium fluorescein and
accumulation of rhodamine 123 in MBEC4 cells.
3. Exposure to CsA significantly decreased the levels of TGF-β1 mRNA in brain pericytes in pericyte co-cultures. Treatment
with TGF-β1 dose-dependently inhibited CsA-induced hyperpermeability and P-glycoprotein dysfunction of MBEC4 cells in pericyte
co-cultures.
4. These findings suggest that an inhibition of brain pericyte-derived TGF-β1 contributes to the occurrence of CsA-induced
dysfunction of the BBB. 相似文献
3.
Transforming growth factor-β (TGF-β) has diverse and multiple roles throughout the body. This review focuses on the evidence
supporting its functions in the central nervous system, with a particular emphasis on its purported role in cerebral ischemia.
Numerous studies have documented that TGF-β1 levels are enhanced in the brain following cerebral ischemia. As evidence that
such an upregulation is beneficial, agonist studies have demonstrated that TGF-β1 reduces neuronal cell death and infarct
size following middle cerebral artery occlusion (MCAO), while conversely, antagonist studies have shown increased neuronal
cell death and infarct size after MCAO. These studies suggest that TGF-β1 has a neuroprotective role in cerebral ischemia.
Recent work with adenoviral-mediated overexpression of TGF-β1 in vivo in mice has further implicated a neuroprotective role
for TGF-β1 in cerebral ischemia, as evidenced by a reduction in neuronal cell death, infarct size, and neurological outcome.
Additionally, numerous in vitro studies have documented the neuroprotective ability of TGF-β1 in neurons from a variety of
species, including rats, mice, chicks, and humans. Of significant interest, TGF-β1 was shown to be protective against a wide
variety of death-inducing agents/insults, including hypoxia/ischemia, glutamate excitotoxicity, β-amyloid, oxidative damage,
and human immunodeficiency virus. The mechanism of TGF-β1-mediated neuroprotection remains to be resolved, but early evidence
suggests that TGF-β1 regulates the expression and ratio of apoptotic (Bad) and antiapoptotic proteins (Bcl-2, Bcl-x1), creating an environment favorable for cell survival of death-inducing insults. Taken as a whole, these results suggest
that TGF-β1 is an important neuroprotective factor that can reduce damage from a wide-array of death-inducing agents/insults
in vitro, as well as exert protection of the brain during cerebral ischemia.
The authors’ research is supported by research grants (HD-28964 and AG-17186 to DWB) from the National Institutes of Health,
NICHD, and NIA. 相似文献
4.
Xu GP Li QQ Cao XX Chen Q Zhao ZH Diao ZQ Xu ZD 《Cellular & molecular biology letters》2007,12(3):457-472
The aim of this study was to investigate whether transforming growth factor-β1 (TGF-β1) could induce alveolar epithelial-mesenchymal
transition (EMT) in vitro, and whether Smad7 gene transfer could block this transition. We also aimed to elucidate the possible mechanisms of these
processes. The Smad7 gene was transfected to the rat type II alveolar epithelial cell line (RLE-6TN). Expression of the EMT-associated
markers was assayed by Western Blot and Real-time PCR. Morphological alterations were examined via phase-contrast microscope
and fluorescence microscope, while ultrastructural changes were examined via electron microscope. TGF-β1 treatment induced
a fibrotic phenotype of RLE-6TN with increased expression of fibronectin (FN), α-smooth muscle actin (α-SMA) and vimentin,
and decreased expression of E-cadherin (E-cad) and cytokeratin19 (CK19). After transfecting the RLE-6TN with the Smad7 gene,
the expression of the mesenchymal markers was downregulated while that of the epithelial markers was upregulated. TGF-β1 treatment
for 48 h resulted in the separation of RLE-6TN from one another and a change into elongated, myofibroblast-like cells. After
the RLE-6TN had been transfected with the Smad7 gene, TGF-β1 treatment had no effect on the morphology of the RLE-6TN. TGF-β1
treatment for 48 h resulted in an abundant expression of α-SMA in the RLE-6TN. If the RLE-6TN were transfected with the Smad7
gene, TGF-β1 treatment for 48 h could only induce a low level of α-SMA expression. Furthermore, TGF-β1 treatment for 12 h
resulted in the degeneration and swelling of the osmiophilic multilamellar bodies, which were the markers of type II alveolar
epithelial cells. TGF-β1 can induce alveolar epithelialmesenchymal transition in vitro, which is dependent on the Smads signaling pathway to a certain extent. Overexpression of the Smad7 gene can partially block
this process 相似文献
5.
Antagonism of Transforming Growth Factor-Β Signaling Inhibits
Fibrosis-Related Genes 总被引:4,自引:0,他引:4
In the fibrotic process, the transforming growth factor-β1 (TGF-β1)/Smad3 (Sma- and Mad-related protein␣3) signaling plays
a central role. To screen for antagonists of TGF-β1/Smad3 signaling and to investigate their effects on the genes related
to fibrosis, we construct a molecular model with a luciferase reporter gene. Results showed that both SB-431542 [4-(5-benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)-benzamide] and small interference RNA (siRNA) against Smad3 could dose-dependently suppress the reporter gene.
More importantly, they both significantly inhibited the expression of plasminogen activator inhibitor-type 1 (PAI-1) and type
I collagenα1 (Col Iα1) genes in rat hepatic stellate cells. Thus, SB-431542 and Smad3/siRNA may be potential therapeutics
for fibrosis. 相似文献
6.
Effects of representative members of the transforming growth factor-β (TGF-β) family, TGF-β1, activin A and BMP-2, on melanin
content and expression of pigment-producing enzymes were examined in B16 melanoma cells. Treatment with TGF-β1 or activin
A but not with BMP-2 significantly decreased melanin content and expression of Tyrosinase and Tyrp-1, suggesting an inhibitory effect of TGF-β1 and activin A on melanin synthesis. TGF-β1 completely inhibited melanin synthesis
induced by α-melanin stimulating hormone (α-MSH), whereas activin A only slightly did. As compared with parental B16 cells,
the inhibitory effects of TGF-β1 and activin A on melanin content were relative smaller in B16 F10 cells, a subline of B16
cells that contain more pigment. The present study indicates that in addition to TGF-β, activin negatively regulates melanogenesis
in the absence of α-MSH, but that the activity in the presence of α-MSH was slightly different between TGF-β and activin. 相似文献
7.
Hiroyuki Kamiguchi Kazunari Yoshida Hirooki Wakamoto Makoto Inaba Hikaru Sasaki Mitsuhiro Otani Shigeo Toya 《Neurochemical research》1996,21(6):701-706
Cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and epidermal growth factor (EGF) are probable factors
responsible for up-regulation of basic fibroblast growth factor (bFGF) expression in reactive astrocytes following brain damage,
however the effect of these cytokines on the expression of each bFGF-isoform has not been elucidated. Western biot analysis
revealed the expression of 18, 22 and 24-kD bFGF isoforms in cultured rat hippocampal astrocytes, and the expression of high
molecular weight (HMW)-isoforms (22 and 24-kD isoforms) but not of 18-kD isoform was selectively increased by cytokines. Immunofluorescent
analysis demonstrated that bFGF content in the cytoplasm of astrocytes is initially increased by cytokines followed by nuclear
targeting and localization in agreement with the previous evidence that HMW-isoforms possess a nuclear targeting signal. The
present results suggest the important role of HMW-bFGF isoforms in the response of nervous tissue to injury. 相似文献
8.
创伤性脑损伤(traumatic brain injury, TBI), 亦称颅脑损伤或头部外伤, 专指由外伤引起的脑组织损害。然而,从轻度到重度的TBI,改善TBI患者预后的治疗方法都十分匮乏。神经炎症可引起脑外伤后急性继发性损伤,并与慢性神经退行性疾病有关,因此,系统了解参与TBI后神经炎性反应的细胞显得尤为重要。主要对TBI中参与炎症反应的细胞(如小胶质细胞、星形胶质细胞、少突细胞、中性粒细胞和淋巴细胞)的启动以及相互作用的最新研究进展进行了综述,以期为临床研究提供新的策略。 相似文献
9.
Lentivirus(LV)-mediated small interfering RNA (siRNA) targeting tumor necrosis factor-α (TNF-α) was locally administered into
the air pouch of mice to inhibit inflammation induced by titanium alloy particles. The lentiviral vector expressed green fluorescent
protein (GFP) as a reporter gene. Down-regulation of TNF-α in pouch area was confirmed by real-time PCR and ELISA, resulting
in significantly decreased local inflammatory responses (P < 0.01). This approach was proven safe by localized GFP fluorescence and invariant TNF-α expression in peripheral blood,
liver, spleen, kidney, lung and brain of mouse. In conclusion, locally administered siRNA provides an effective and safe method
for inhibiting particle-induced inflammation. 相似文献
10.
Yukari Komuta Xichuan Teng Hiroko Yanagisawa Kazunori Sango Koki Kawamura Hitoshi Kawano 《Cellular and molecular neurobiology》2010,30(1):101-111
The fibrotic scar which is formed after traumatic damage of the central nervous system (CNS) is considered as a major impediment
for axonal regeneration. In the process of the fibrotic scar formation, meningeal fibroblasts invade and proliferate in the
lesion site to secrete extracellular matrix proteins, such as collagen and laminin. Thereafter, end feet of reactive astrocytes
elaborate a glia limitans surrounding the fibrotic scar. Transforming growth factor-β1 (TGF-β1), a potent scar-inducing factor,
which is upregulated after CNS injury, has been implicated in the formation of the fibrotic scar and glia limitans. In the
present study, expression of receptors to TGF-β1 was examined by in situ hybridization histochemistry in transcortical knife
lesions of the striatum in the mouse brain in combination with immunofluorescent staining for fibroblasts and astrocytes.
Type I and type II TGF-β receptor mRNAs were barely detected in the intact brain and first found in meningeal cells near the
lesion 1 day postinjury. Many cells expressing TGF-β receptors were found around the lesion site 3 days postinjury, and some
of them were immunoreactive for fibronectin. After 5 days postinjury, many fibroblasts migrated from the meninges to the lesion
site formed the fibrotic scar, and most of them expressed TGF-β receptors. In contrast, few of reactive astrocytes expressed
the receptors throughout the postinjury period examined. These results indicate that meningeal fibroblasts not reactive astrocytes
are a major target of TGF-β1 that is upregulated after CNS injury. 相似文献
11.
Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that plays a critical role in modulating immune response and
inflammation. We have investigated the effects of TGF-β1 on the expression of type IV collagenases, matrix metalloproteinase
(MMP)-2 and MMP-9, in mouse peritoneal macrophages. TGF-β1 alone enhanced the secretion of MMP-9, while it blocked lipopolysaccharide
(LPS)-stimulated MMP-9 production. We have shown that this biphasic effect of TGF-β1 is exerted at the mRNA level of the MMP-9
gene. Although TGF-β1 increased both basal and LPS-induced MMP-2 production at the protein and mRNA levels, the extent of
the increase was smaller in LPS-activated macrophages than in control macrophages. The expression of type I and type II receptors
for TGF-β was significantly decreased upon activation, suggesting that the lesser effect of TGF-β1 in activated macrophages
may result from the decreased expression of TGF-β receptors. In addition, the expression of endogenous TGF-β1 mRNA was decreased
significantly in activated macrophages. These findings suggest that activated macrophages not only produce less TGF-β1, but
also respond less well to TGF-β to provide for inflammatory response. 相似文献
12.
Transforming growth factor-β (TGF-β) is a central regulator in chronic liver disease contributing to all stages of disease
progression from initial liver injury through inflammation and fibrosis to cirrhosis and hepatocellular carcinoma. Liver-damage-induced
levels of active TGF-β enhance hepatocyte destruction and mediate hepatic stellate cell and fibroblast activation resulting
in a wound-healing response, including myofibroblast generation and extracellular matrix deposition. Being recognised as a
major profibrogenic cytokine, the targeting of the TGF-β signalling pathway has been explored with respect to the inhibition
of liver disease progression. Whereas interference with TGF-β signalling in various short-term animal models has provided
promising results, liver disease progression in humans is a process of decades with different phases in which TGF-β or its
targeting might have both beneficial and adverse outcomes. Based on recent literature, we summarise the cell-type-directed
double-edged role of TGF-β in various liver disease stages. We emphasise that, in order to achieve therapeutic effects, we
need to target TGF-β signalling in the right cell type at the right time. 相似文献
13.
Peng Qi Yue-ming Chen Hao Wang Meng Fang Qiang Ji Yun-peng Zhao Xiao-juan Sun Yan Liu Chun-fang Gao 《Cancer immunology, immunotherapy : CII》2009,58(9):1433-1440
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The risk for developing HCC increases
with severity of inflammation and fibrosis. Transforming growth factor-β1 (TGF-β1) is most frequently upregulated in tumor
cells. The most studied −509C>T polymorphism of TGF-β1 gene has been associated with colorectal, gynecologic, and lung cancers.
To assess whether this polymorphism in TGF-β1 gene is associated with susceptibility to and/or clinicopathologic characteristics
of HBV-related HCC, a total of 575 patients with chronic HBV infection and 299 healthy volunteers with no evidence of recent
or remote HBV infection were prospectively enrolled. The patients were divided into two groups: those without (n = 196) and those with HCC (n = 379). These 379 HCC patients with chronic HBV infection were designated as cases, the remaining 196 patients without HCC
and 299 healthy volunteers served as disease and healthy controls, respectively. −509C>T polymorphism in the TGF-β1 gene promoter
was studied using restriction fragment-length polymorphism. In addition, tumor tissues of liver (n = 60) were obtained from the studied HCC patients for measurement of TGF-β1 mRNA expression levels. We also assessed the
plasma TGF-β1 levels of HBV patients without (n = 94) or with HCC (n = 136) and healthy subjects (n = 120). In our study group, the risk of HCC in Chinese patients with HBV infection was significantly lower with the TT genotypes
than in those with the CC genotypes at position −509 of TGF-β1 gene (P = 0.01). In addition, in the case group, patients with the CC genotype had a statistically significant higher median plasma
TGF-β1 or liver tumor tissue TGF-β1 mRNA level compared with the individuals with the TT genotype. However, in a subsequent
analysis of the association between this polymorphism and clinicopathological characteristics including tumor number, size,
grade, stage, and invasiveness, there was no significant difference in both the distribution of genotype or allelic frequency
within HCC patients, indicating that −509C>T exchange in TGF-β1 gene may play an important role in the occurrence, not the
progression of HBV-related HCC through influencing plasma concentrations of TGF-β1 or TGF-β1 mRNA expression of liver tumor
tissue. 相似文献
14.
Joanna Szmydynger-Chodobska Jessica R. Gandy Andrew Varone Rongzi Shan Adam Chodobski 《PloS one》2013,8(11)
Several lines of evidence indicate that the blood-cerebrospinal fluid barrier (BCSFB), which primarily resides in the choroid plexus (CP), plays a significant pathophysiological role not only in neuroinflammatory diseases, such as multiple sclerosis, but also in traumatic brain injury (TBI). Here we investigated how arginine vasopressin (AVP) regulates function of the BCSFB in the context of post-traumatic neuroinflammation. It has previously been shown that AVP exacerbates various forms of brain injury, but the mechanisms underlying this AVP action are poorly understood. Type 1A AVP receptor is highly expressed on the CP epithelium and the CP synthesizes AVP. Using the controlled cortical impact model of TBI, we demonstrated decreased post-traumatic production of proinflammatory mediators by the CP and reduced influx of inflammatory cells across the BCSFB in AVP-deficient Brattleboro rats when compared with Long-Evans rats, a parental strain for Brattleboro rats. Arginine vasopressin was also found to play an important role in post-traumatic activation of c-Jun N-terminal kinase (JNK) in the CP. In the CP epithelial cell cultures, AVP augmented the tumor necrosis factor-α– and interleukin-1β–dependent increase in synthesis of proinflammatory mediators, including neutrophil chemoattractants, an action largely dependent on the JNK signaling pathway. Under in vivo conditions, a selective JNK inhibitor decreased the post-traumatic production of neutrophil chemoattractants by the CP and reduced the influx of neutrophils across the BCSFB. These results provide evidence for the synergistic interactions between proinflammatory cytokines and AVP, a ligand for G protein-coupled receptors, and support a pathophysiological role of AVP in post-traumatic neuroinflammation. 相似文献
15.
Zhao XY Zhao LY Zheng QS Su JL Guan H Shang FJ Niu XL He YP Lu XL 《Molecular and cellular biochemistry》2008,310(1-2):159-166
Mast cell-derived chymase is implicated in myocardial fibrosis (MF), but the underlying mechanism of intracellular signaling
remains unclear. Transforming growth factor-β1 (TGF-β1) is identified as the most important profibrotic cytokine, and Smad
proteins are essential, but not exclusive downstream components of TGF-β1 signaling. Moreover, novel evidence indicates that
there is a cross talk between Smad and mitogen-activated protein kinase (MAPK) signaling cascade. We investigated whether
chymase activated TGF-β1/Smad pathway and its potential role in MF by evaluating cardiac fibroblasts (CFs) proliferation and
collagen synthesis in neonatal rats. MTT assay and 3H-Proline incorporation revealed that chymase induced CFs proliferation and collagen synthesis in a dose-dependent manner.
RT-PCR and Western blot assay demonstrated that chymase not only increased TGF-β1 expression but also upregulated phosphorylated-Smad2/3
protein. Furthermore, pretreatment with TGF-β1 neutralizing antibody suppressed chymase-induced cell growth, collagen production,
and Smad activation. In contrast, the blockade of angiotensin II receptor had no effects on chymase-induced production of
TGF-β1 and profibrotic action. Additionally, the inhibition of MAPK signaling had no effect on Smad activation elicited by
chymase. These results suggest that chymase can promote CFs proliferation and collagen synthesis via TGF-β1/Smad pathway rather
than angiotensin II, which is implicated in the process of MF. 相似文献
16.
Minoru Morikawa Naoki Harada Gen-Ichiro Soma Takeshi Yoshida 《In vitro cellular & developmental biology. Plant》1990,26(7):682-690
Summary The human leukemic cells HL-60, U937, KG-1 and THP-1 incubated with transforming growth factor-β1 (TGF-β1) were studied by
examining cell surface antigens and macrophage-specific activities. The addition of 0.5 ng/ml (20 pM) of TGF-β1 with 1α,25-dihydroxyvitamin D3 [1α, 25(OH)2D3] induced more Leu-M3 (CD14)-positive cells (approximately 80%) than 5×10−8
M 1α,25(OH)2D3 alone did (30 to 50%), although original HL-60 cells did not express any Leu-M3 antigen at all. Tumor necrosis factor-α (TNF-α)
with TGF-β1 and 1α,25(OH)2D3 was found to potentiate the expression of these surface antigens. Furthermore, the phagocytic activity was also induced strongly.
The expression of CR3 (CD11b) antigen was also increased, and all Leu-M3-positive cells were found CR3-positive when HL-60,
U937, and THP-1 cells were treated with these stimulants. In contrast, CR3 but not Leu-M3 was induced in KG-1 cells after
the same treatment. This may indicate that the responsiveness of leukemic cells to TGF-β1 and 1α,25(OH)2D3 might vary depending on a differentiation stage of the target cells. Furthermore, K562 cells originated from a more undifferentiated
precursor, were not able to respond to these two inducers. These results suggested that some of TGF-β superfamily proteins
might represent potent modulators in hematopoiesis, especially in the development of monocytes-macrophages or their precursors. 相似文献
17.
Honglu Chao Yinlong Liu Chao Lin Xiupeng Xu Zheng Li Zhongyuan Bao Liang Fan Chao Tao Lin Zhao Yan Liu Xiaoming Wang Yongping You Ning Liu Jing Ji 《生物化学与生物物理学报:疾病的分子基础》2018,1864(9):2957-2971
Phospholipase A2 is a known aggravator of inflammation and deteriorates neurological outcomes after traumatic brain injury (TBI), however the exact inflammatory mechanisms remain unknown. This study investigated the role of bradykinin and its receptor, which are known initial mediators within inflammation activation, as well as the mechanisms of the cytosolic phospholipase A2 (cPLA2)-related inflammatory responses after TBI. We found that cPLA2 and bradykinin B2 receptor were upregulated after a TBI. Rats treated with the bradykinin B2 receptor inhibitor LF 16-0687 exhibited significantly less cPLA2 expression and related inflammatory responses in the brain cortex after sustaining a controlled cortical impact (CCI) injury. Both the cPLA2 inhibitor and the LF16-0687 improved CCI rat outcomes by decreasing neuron death and reducing brain edema. The following TBI model utilized both primary astrocytes and primary neurons in order to gain further understanding of the inflammation mechanisms of the B2 bradykinin receptor and the cPLA2 in the central nervous system. There was a stronger reaction from the astrocytes as well as a protective effect of LF16-0687 after the stretch injury and bradykinin treatment. The protein kinase C pathway was thought to be involved in the B2 bradykinin receptor as well as the cPLA2-related inflammatory responses. Rottlerin, a Protein Kinase C (PKC) δ inhibitor, decreased the activity of the cPLA2 activity post-injury, and LF16-0687 suppressed both the PKC pathway and the cPLA2 activity within the astrocytes. These results indicated that the bradykinin B2 receptor-mediated pathway is involved in the cPLA2-related inflammatory response from the PKC pathway. 相似文献
18.
Caraci F Spampinato S Sortino MA Bosco P Battaglia G Bruno V Drago F Nicoletti F Copani A 《Cell and tissue research》2012,347(1):291-301
Alzheimer’s disease (AD) is a neurodegenerative disorder that affects about 35 million people worldwide. Current drugs for
AD only treat the symptoms and do not interfere with the underlying pathogenic mechanisms of the disease. AD is characterized
by the presence of β-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Identification of the molecular determinants
underlying Aβ-induced neurodegeneration is an essential step for the development of disease-modifying drugs. Recently, an
impairment of the transforming growth factor-β1 (TGF-β1) signaling pathway has been demonstrated to be specific to the AD
brain and, particularly, to the early phase of the disease. TGF-β1 is a neurotrophic factor responsible for the initiation
and maintenance of neuronal differentiation and synaptic plasticity. The deficiency of TGF-β1 signaling is associated with
Aβ pathology and neurofibrillary tangle formation in AD animal models. Reduced TGF-β1 signaling seems to contribute both to
microglial activation and to ectopic cell-cycle re-activation in neurons, two events that contribute to neurodegeneration
in the AD brain. The neuroprotective features of TGF-β1 indicate the advantage of rescuing TGF-β1 signaling as a means to
slow down the neurodegenerative process in AD. 相似文献
19.
Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute-phase response 总被引:1,自引:0,他引:1
Campbell SJ Jiang Y Davis AE Farrands R Holbrook J Leppert D Anthony DC 《Journal of neurochemistry》2007,103(6):2245-2255
TNF-α has proved to be a successful target in the treatment of many peripheral inflammatory diseases, but the same interventions worsen immune-mediated CNS disease. However, anti-TNF-α strategies may offer promise as therapy for non-immune CNS injury. In this study, we have microinjected IL-1β or lipopolysaccharide (LPS) into the rat brain as a simple model of brain injury and have systemically administered the TNF-α antagonist etanercept to discover whether hepatic TNF-α, produced as part of the acute-phase response to CNS injury, modulates the inflammatory response in the brain. We report a significant reduction in neutrophil numbers recruited to the IL-1β- or LPS-challenged brain as a result of TNF-α inhibition. We also show an attenuation in the levels of hepatic mRNA including TNF-α mRNA and of TNF-α-induced genes, such as the chemokines CCL-2, CXCL-5, and CXCL-10, although other chemokines elevated by the injury were not significantly changed. The reduction in hepatic chemokine synthesis results in reduced numbers of circulating neutrophils, and also a reduction in the numbers recruited to the liver as a consequence of brain injury. These findings suggest that TNF-α inhibitors may reduce CNS inflammatory responses by targeting the hepatic acute-phase response, and thus therapies for brain injury need not cross the blood–brain barrier to be effective. 相似文献
20.
Riera KM Rothfusz NE Wilusz RE Weinberg JB Guilak F McNulty AL 《Arthritis research & therapy》2011,13(6):R187