Transforming Growth Factor-??1???Modulated Cerebral Gene Expression (original) (raw)
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Transforming growth factor-β and ischemic brain injury
2003
1. Necrosis and apoptosis are the two fundamental hallmarks of neuronal death in stroke. Nevertheless, thrombolysis, by using the recombinant serine protease t-PA, remains until now the only approved treatment of stroke in man.
Transforming growth factor-β1 exhibits delayed gene expression following focal cerebral ischemia
Brain Research Bulletin, 1995
Transfmlning growth factor-~l (TGF-pl) is a pleiotropic peptide growth factor. The expression of TGF-pl mRNA in the focal ~ cortex of rats was studied by means of Nornw, h,~xk~tim. A modmt~ k)w k,~ of c(mt~,v~ expressed TGF-~I1 mRNA was det~tml following sham-surgery or in the co.;iidalafal (nmgschemic) cortex. A idgnifi~nt inoremm of TGF-/ll mRNA Iovel in the ischemic cortox was ob-~ed at 2 days (&2-tokl k.:me~ =~.pared to dmn-opormd animlds, p < 0.01, n = 4) folBowing permanent occlusion of Ule middle cerebral artmy (PMCAO). The elevabld TGF~I1 mRNA expression was plateaued for up to 15 days (3.6-told increase, p < 0.01) following PMCAO. This m profile for TGF-~I mRNA exlxeasion in focal stroke was signiflcanUy delayed compared to that of TNF-a, IL-lp and IL-6 mRNA eXlXassions as demonslbrated prevlomdy which peaked at 12 h and deceeased to aknost basa lewas by S dws falowing PMeAO. Wcmmnngly. the TGF-,81 mRNA exlx'oeaton profile was mmmtudl~ parallel with that of monocyte/~ a~:tamdation in the ischemic cortex, as well as with the increased formation of exll~-ceUular matdx in the focal ischemtc bra~ Thase data suggast that TGF-/I1 may ptay a role in anti-inflammatory process and in tissue remodeling following ischemic brain injury.
Molecular Brain Research, 1996
Although transforming growth factor-[~ is known to be multifunctional in many physiological systems, its role in the brain is undergoing elucidation. The situation is made more complex by the presence of multiple isoforms, which may be differentially regulated and have various activities in each particular cell type. Because neurons are dependent on neurotrophic factors for survival, we utilized a rat model of transient forebrain ischemia (TFI) to test the hypothesis that TGF-[3 isoforms are important in the hippocampal response to injury. Northern blot analysis demonstrated a differential and temporal alteration in TGF-[3 isoform expression following TFI. In-situ hybridization experiments revealed that at day 1 following TFI, there was a strong neuronal increase in the TGF[3-1 transcript but a reciprocal decrease in TGF-[32 and -[33 transcript levels. Immunohistochemical analysis of all three TGF-[3s demonstrated at day 1 following TFI a loss of the immunoreactive proteins in the vulnerable CA-1 hippocampal neurons, but protein preservation in the CA-2-4 neurons which are more resistant to the ischemic insult. At 3-5 days following TFI, significant extraneuronal changes in TGF-[3 isoform expression were also detected. Double-staining experiments with antibody to glial fibrillary acidic protein (GFAP) as a marker for astrocytes, and lectin isolectin B4 Griffonia simplicifolia for microglia, demonstrated increased expression of all TGF-[3 isoforms in astrocytes but not microglia. Taken together, these results suggest that the TGF-[3 peptides in neurons and astrocytes are important endogenous mediators in the CNS response to ischemic injury.
Transforming growth factor-β signalling in brain disorders
Cytokine & Growth Factor Reviews, 2006
Transforming growth factor-b (TGF-b) has been characterized as an injury-related factor, based on the observation that it is strongly upregulated in many acute or chronic central nervous system disorders. TGF-b is generally thought to be neuroprotective and several mechanisms have been proposed to explain this beneficial action. For instance, TGF-b protects neurons against the potentiating effect of tissue-type plasminogen activator on NMDA receptor-mediated excitotoxicity, by up-regulating type-1 plasminogen activator inhibitor expression in astrocytes. TGF-b has also anti-apoptotic properties, through a recruitment of a mitogen-activated protein kinase pathway and a concomitant activation of anti-apoptotic members of the Bcl-2 family. These multiple mechanisms might reflect the pleiotropic nature of TGF-b, reinforcing the potential therapeutic value of this cytokine in several central nervous system disorders. #
Acta Neuropathologica, 1993
Using an RNAse protection assay, expression of messenger RNA for isoforms of TGF-P was determined in a series of breast cancers. Of 50 tumours, 45 (90%) expressed TGF-P, mRNA, 39 (78%) expressed TGF-P2, and 47 (94%) expressed TGF-P3. Patterns of expression varied between different tumours: 37 (74%) cancers expressed all three TGF-P isoforms, ten (20%) expressed only two isoforms and two expressed TGF-P, alone. One sample showed no evidence of TGF-P mRNA expression. Although most breast cancers expressed mRNA for at least one isoform of TGF-P, there were differences in patterns of mRNA expression between individual tumours. The relatively small number of tumours examined precluded detailed analysis between expression and other clinical parameters, but a significant association was identified between one aspect of isoform expression and lymph node status, in that the majority of tumours expressing all three isoforms were associated with lymph node involvement, whereas tumours without one or more isoform were usually lymph node negative (P = 0.025 by Fisher's exact test).
Transforming growth factor-β1 potentiates amyloid-β generation in astrocytes and in transgenic mice
2003
Accumulation of the amyloid- peptide (A) in the brain is crucial for development of Alzheimer's disease. Expression of transforming growth factor-1 (TGF-1), an immunosuppressive cytokine, has been correlated in vivo with A accumulation in transgenic mice and recently with A clearance by activated microglia. Here, we demonstrate that TGF-1 drives the production of A40/42 by astrocytes leading to A production in TGF-1 transgenic mice. First, TGF-1 induces the overexpression of the amyloid precursor protein (APP) in astrocytes but not in neurons, involving a highly conserved TGF-1-responsive element in the 5-untranslated region (؉54/؉74) of the APP promoter. Second, we demonstrated an increased release of soluble APP- which led to TGF-1-induced A generation in both murine and human astrocytes. These results demonstrate that TGF-1 potentiates A production in human astrocytes and may enhance the formation of plaques burden in the brain of Alzheimer's disease patients. The proteolytic cleavage of the amyloid precursor protein (APP) 1 leads to the production of A with a large amount of the 40-amino acid variant, A40, and to a lesser extent of the 42-amino acid variant, A42. In Alzheimer's disease, this amyloidogenesis can lead to the formation of amyloid deposits within the cerebral parenchyma and vascular walls (1, 2). Many studies have identified increased levels of a variety of cytokines in patients developing chronic neurodegenerative disorders such as AD (3-8). Among these factors, recent reports have associated transforming growth factor-1 (TGF-1), a potent immunosuppressive cytokine, with AD. First, recent data suggest that a genetic polymorphism of the TGF-1 gene may be associated with a higher risk to develop AD (9). Second, post-mortem brain tissue analyses of AD patients show an increased expression of TGF-1 correlated with the degree of cerebral amyloid angiopathy (8). Third, 16-month-old transgenic mice overexpressing TGF-1 in astrocytes elicit A deposition (8). In the same study, these authors generated biogenic mice expressing both human APP and TGF-1. In these hAPP/ TGF-1 mice, A deposits were observed after 3 months of age compared with TGF-1 mice, suggesting that TGF-1 would be able to influence APP metabolism or processing. In addition to its amyloidogenic effects (8), TGF-1 was recently associated with A clearance from the brain parenchyma to the cerebral blood vasculature in aged hAPP/TGF-1 mice by activated microglia (10). Despite this dual effect of TGF-1 in the amyloid plaque metabolism, the mechanism(s) by which TGF-1 promotes the production of A remained to be elucidated. EXPERIMENTAL PROCEDURES Semiquantitative Reverse Transcription-PCR (RT-PCR)-Total RNAs were prepared using either the RNAxel extraction kit (Eurobio, Paris, France) or RNAeasy extraction columns (Qiagen, Courtaboeuf, France). Samples (1 g) of total mRNA were transcribed into cDNA. cDNA libraries (1 l from 20 l) were amplified by PCR with oligonucleotides for -actin, APP 770 , APP 751 , and APP 695 (respectively 539, 242, 222, and 401 bp of PCR products). All PCR were established in the linear range of amplification by performing multicycle amplification to reach half of the saturation curve. The -actin oligonucleotides were:
Neuroscience Letters, 2008
Alzheimer's disease (AD) is a neurodegenerative disorder, due to excess amyloid- peptide (A). TGF-1 and -catenin signaling pathways have been separately implicated in modulating A-neurotoxicity. However, the underlying mechanisms remain unclear. Here, we report that TGF-1 and nuclear Smad7 and -catenin levels were markedly upregulated in cortical brain regions of the TgCRND8 mice, a mouse model of familial Alzheimer's disease. Coimmunoprecipitation of cortical brain tissue lysates revealed an interaction between Smad7 and -catenin. This interaction which was significantly enhanced in the TgCRND8 mice was also associated with an increase in TCF/LEF DNA-shift binding activity. TCF/LEF reporter gene activity was significantly increased in mouse primary cortical neuronal cultures (MCN) from the TgCRND8 mice, compared to controls. Interestingly, exposure of MCN to A 1-42 led to an increase in TGF-1 and nuclear levels of both -catenin and Smad7. Furthermore, addition of TGF-1 to the MCN caused an increase in apoptosis and Smad7 levels. When Smad7 or -catenin levels were reduced by siRNA, TGF-1-induced apoptosis was suppressed, indicating that both Smad7 and -catenin are required for TGF-1-induced neurotoxicity. Since A 1-42-induced TGF-1, we suggest that TGF-1 may amplify A 1-42-mediated neurodegeneration in AD via Smad7 and -catenin interaction and nuclear localization.
Journal of Cerebral Blood Flow & Metabolism, 1999
Various studies describe increased concentrations of transforming growth factor-13 (TGF-I3) in brain tissue after acute brain injury. However, the role of endogenously pro duced TGF-13 after brain damage to the CNS remains to be clearly established. Here, the authors examine the influence of TGF-13 produced after an episode of cerebral ischemia by in jecting a soluble TGF-13 type II receptor fused with the Fc region of a human immunoglobulin (TI3RIIs-Fc). First, this molecular constll'ct was characterized as a selective antagonist of TGF-I3. Then, the authors tested its ability to reverse the effect of TGF-13 1 on excitotoxic cell death in murine cortical cell cultures. The addition of 1 j.Lg/mL of TI3RIIs-Fc to the exposure medium antagonized the neuroprotective activity of TGF-13 1 in N-methyl-D-aspartate (NMDA)-induced excitotoxic cell death. These results are consistent with the hypothesis that TGF-13 1 exerts a negative modulatory action on NMDA recep tor-mediated excitotoxicity. To determine the role of TGF-13 1 produced in response to brain damage, the authors used a model of an excitotoxic lesion induced by the intrastriatal injection of 75 nmol of NMDA in the presence of 1.5 j.Lg of TI3RIIs-Fc. The It is well accepted that the toxic overstimulation of postsynaptic glutamate receptors may contribute to pathologic neuronal death resulting from certain acute insults to the CNS, including hypoglycemia, hypoxia ischemia, trauma, and spinal cord injury (Choi et aI., 1992). Such forms of excitotoxic neuronal death are me-Abbreviations used: AMPA, a-amino-3-hydroxy-5-methyl-4isoxazolepropionate; LDH, lactate dehydrogenase; MCAO, middle ce rebral artery occlusion; MS, media stock; NMDA, N-methyl-D aspartate; PCR, polymerase chain reaction; TbR, TGF-�-responsive cells; TGF-�, transforming growth factor-�. 1345 intrastriatal injection of NMDA was demonstrated to induce an early upregulation of the expression of TGF-13 1 mRNA. Fur thermore, when added to the excitotoxin, TI3RIIs-Fc increased (by 2.2-fold, P < 0.05) the lesion size. These observations were strengthened by the fact that an intracortical injection of TI3RIIs-Fc in rats subjected to a 30-minute reversible cerebral focal ischemia aggravated the volume of infarction. In the group injected with the TGF-13 1 antagonist, a 3.5-fold increase was measured in the infarction size (43.3 ± 9.5 versus 152.8 ± 46.3 mm 3 ; P < 0.05). In conclusion, by antagonizing the influ ence of TGF-13 in brain tissue subjected to excitotoxic or isch emic lesion, the authors markedly exacerbated the resulting extent of necrosis. These results suggest that, in response to such insults, brain tissue responds by the synthesis of a neuro protective cytokine, TGF-131, which is involved in the limita tion of the extent of the injury. The pharmacologic potentiation of this endogenous defensive mechanism might represent an alternative and novel strategy for the therapy of hypoxic ischemic cerebral injury.