Heh, in keeping with my theme of the day, Henson even states here, "there is considerable evidence to implicate PS as the main stimulus for the anti-inflammatory or anti-immunogenic effects"
In the studies reported here, we showed that the TGF-beta induction by apoptotic cells was dependent on exposed PS
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These results strongly suggest that the apoptotic cell inhibition of pro-inflammatory mediator production is pleiotropic and significantly dependent on the stimulation of TGF-beta production.
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The implication is that recognition of PS drives the production of TGF-beta and the downstream antiinflammatory responses reported herein.
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The induction of TGF-beta itself could be attributed to exposed phosphatidylserine on the apoptotic cells, which therefore, appears to drive the balanced inflammatory mediator responses.
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Apoptotic cells are rapidly engulfed by adjacent tissue cells or macrophages before they can release pro-inflammatory/proimmunogenic intracellular contents. In addition, recognition of the apoptotic cells is actively anti-inflammatory and antiimmunogenic with generation of antiinflammatory mediators such as transforming growth factor-beta (TGF-beta) and anti-inflammatory eicosanoids. Here, we have investigated the role played by the induction of TGF-beta in the coordinate expression of antiinflammatory eicosanoids or PPARγ and in the suppression of pro-inflammatory lipid mediators and nitric oxide (NO).
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As a cell becomes apoptotic, it is generally removed in situ by near-neighbor cells or macrophages in a quiet, almost invisible fashion; that is, the process does not induce a local tissue reaction. In fact, recognition and removal of apoptotic cells is normally both anti-inflammatory and anti-immunogenic (6-9).
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The interaction and recognition are triggered by surface changes on the apoptotic cells.
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there is considerable evidence to implicate PS as the main stimulus for the anti-inflammatory or anti-immunogenic effects (6-8,14-16).
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A major anti-inflammatory mediator induced in response to apoptotic cells, mAb217 or PS liposomes is TGF-beta (6,8,16). Blockade of TGF- beta has been shown to reverse the suppressive effects of apoptotic cells or PS in vivo on either inflammation or adaptive immunity (7,8).
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A key issue, therefore, is whether apoptotic cellinduced TGF-beta, acting in an autocrine/paracrine fashion, mediates the alterations in eicosanoid generation. By use of a dominant negative TGF- beta receptor construct we have been able to show that apoptotic cells stimulate via their induction of active TGF-beta, a co-ordinate production of generally anti-inflammatory, and simultaneous inhibition of generally pro-inflammatory, eicosanoids.
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Results Apoptotic cells or antibody to PSRS on murine macrophages stimulate production of TGF- beta and concomitant blockade of LPS-induced TNF alpha, NO and iNOS.
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Discussion Apoptotic cells are known to induce an antiinflammatory and anti-immunogenic response, in part mediated by their induction of active TGF-beta in responding cells. Here we show that the effect of the apoptotic cells is to drive a complex coordinated inhibition of potentially inflammatory mediators along with induction of potentially anti-inflammatory molecules in macrophages that are orchestrated by the TGF-beta production.
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The observations required the demonstration of TGF-beta production in response to the apoptotic cells – shown earlier by numerous investigators and confirmed herein. A number of ligands have been demonstrated on apoptotic cells that can interact with a number of “receptors” on responding cells, in this case macrophages. Additionally there are a large group of “bridge” molecules (see ref. 39) that can link the apoptotic cell ligands to the receptors. We have suggested that two important ligands are phosphatidylserine (PS) and calreticulin. The latter, as well as the collectin family of bridge molecules (40) has been suggested to interact with LRP as a receptor and, in isolation, seems to induce a more pro-inflammatory response (5,13). On the other hand, PS and its receptors and possibly some or all of its bridge molecules appear to induce the anti-inflammatory effects and, in most cases, to act in a dominant fashion in the normal response to apoptotic cells. Necrotic cells are usually thought to be proinflammatory (see for example 9,15) and may have reversed this PS-driven dominance. Other studies that have suggested that apoptotic cells can in some circumstances act in a proinflammatory fashion may also reflect variations in balance between pro-inflammatory (e.g. LRP) versus anti-inflammatory (e.g. PS driven) responses.
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The results indicate a complex effect of apoptotic cells acting through release of TGF-beta to upregulate generally anti-inflammatory mediators and inhibit the production of proinflammatory molecules.
Mechanisms underlying TGF-{beta}1-induced expression of VEGF and Flk-1 in mouse macrophages and their implications for angiogenesis.
* Jeon SH, * Chae BC, * Kim HA, * Seo GY, * Seo DW, * Chun GT, * Kim NS, * Yie SW, * Byeon WH, * Eom SH, * Ha KS, * Kim YM, * Kim PH.
School of Bioscience and Biotechnology, Kangwon National University, Chunchon 200-701, Korea
TGF-beta induces vascular endothelial growth factor (VEGF), a potent angiogenic factor, at the transcriptional and protein levels in mouse macrophages. VEGF secretion in response to TGF-beta1 is enhanced by hypoxia and by overexpression of Smad3/4 and hypoxia-inducible factor-1alpha/beta (HIF-1alpha/beta). To examine the transcriptional regulation of VEGF by TGF-beta1, we constructed mouse reporters driven by the VEGF promoter. Overexpression of HIF-1alpha/beta or Smad3/4 caused a slight increase of VEGF promoter activity in the presence of TGF-beta1, whereas cotransfection of HIF-1alpha/beta and Smad3/4 had a marked effect. Smad2 was without effect on this promoter activity, whereas Smad7 markedly reduced it. Analysis of mutant promoters revealed that the one putative HIF-1 and two Smad-binding elements were critical for TGF-beta1-induced VEGF promoter activity. The relevance of these elements was confirmed by chromatin immunoprecipitation assay. p300, which has histone acetyltransferase activity, augmented transcriptional activity in response to HIF-1alpha/beta and Smad3/4, and E1A, an inhibitor of p300, inhibited it. TGF-beta1 also increased the expression of fetal liver kinase-1 (Flk-1), a major VEGF receptor, and TGF-beta1 and VEGF stimulated pro-matrix metalloproteinase 9 (MMP-9) and active-MMP-9 expression, respectively. The results from the present study indicate that TGF-beta1 can activate mouse macrophages to express angiogenic mediators such as VEGF, MMP-9, and Flk-1.
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