The lesions of fibrocontractive diseases result from an excessive myofibroproliferative response to numerous forms of inflammatory stimuli, which elicit the net deposition of extracellular matrix (ECM) in the interstitium of the affected tissue. Hyaluronan (HA), reported to be a key player supporting cellular migration and adherence, is a major component of ECM that undergoes dynamic regulation during inflammation. The molecular regulation of HA biosynthesis by inflammatory cytokines on myofibroblasts is not yet completely understood. Here we report the biochemical characteristics of the lung myofibroblast cell line MRC-5, and we demonstrate that the production of HA by this cell line is inducible by the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), at the message level of HA synthase (HAS). In TNF-alpha-stimulated MRC-5 cells, DNA-binding and competition experiments indicated that the predominant NF-kappa B binding activity detected with nuclear extract-stimulated cells is mediated by the p50/p65 complex. Using antisense oligonucleotides, we confirmed that the TNF-alpha-stimulation of HA synthesis by MRC-5 cells is dependent on the activation of the p50/p65 NF-kappa B complex. These findings indicate that TNF-alpha production within inflamed tissues may enhance the HA synthesis via the transcriptional induction of HAS on myofibroblasts, thereby providing a provisional matrix for supporting cellular migration and adhesion, and that the p50/p65 NF-kappa B complex that plays an important role in the regulation of HA production by TNF-alpha might be an appropriate target for therapeutic compounds to treat tissue fibrosis accompanied by inflammation.
We investigated the effect of transforming growth factor-beta1 (TGF-beta1) on the expression of calponin-h1, alpha-smooth muscle actin (alpha-SMA), and extracellular matrix (ECM) components in a cultured human Ito cell line, LI90. The TGF-beta1 treatment stimulated productions of hyaluronic acid and laminin, and significantly decreased the secretion of hepatocyte growth factor in LI90 cells. The functional characteristics of LI90 cells were compatible with those of human-activated Ito cells that are known as pericyte-like mesenchymal liver cells. TGF-beta1 induced a slight growth-inhibition of LI90 cells. TGF-beta1 enhanced the expressions of both alpha-SMA and calponin-h1 at the protein level, while tumor necrosis factor-alpha and interleukin-1alpha did not affect the expressions of these cytoskeletal proteins on LI90 cells. The addition of TGF-beta1 to LI90 cells resulted in a significant increase of calponin-h1 mRNA levels, but not calponin-h2. These data suggest that the expression of calponin-h1 is controlled at the level of mRNA under the coordinate regulation together with alpha-SMA as the process of perpetuation of activated Ito cells promoted by TGF-beta1. The identification of smooth muscle features promoted by TGF-beta1 support the hypothesis that the activation of Ito cells coincides with their contractile behavior, indicating that these cells may be important in vasoregulation during liver injury and fibrosis.
SUMMARYWe investigated the levels of TGF-/? in malignant pleural effusions (MPE) caused by malignant mesothelioma (MESO) or primary lung cancer. TGF-/? levels in MPE caused by MESO were 283-9 ± 219-2pM (mean is.d.) and were three to six times higher than those due to primary lung cancers (P < 0-01 or P < 0-05). We also evaluated TGF-/?1-and /32-like activities in MPE using specific polyclonal antibodies. Although TGF-/?l-like activity could be detected in all cases, TGF-^2-like activities were detected in five of seven in MESO and in a few cases with primary lung cancer. These results demonstrate that the levels of total TGF-/? and TGF-/?2-like activity may be clinically useful to differentiate MESO from primary lung cancer. Our data also suggest that TGF-/? may help further characterize the clinical features of MESO.Keywords TGF-jSl TGF-,32 malignant pleural effusion malignant mesothelioma primary lung cancer
SUMMARYTransforming growth factor-beta (TGF-/J) is one ofthe cytokines whieh play an immunosuppressive role in an inflammatory process. To investigate the local production of TGF-/i. we evaluated the levels of TGF-/J in tuberculous picural effusions (TBPH) and non-tuberculous benign pleura! effusions (non-TBPE) by the growth inhibition assay with MvlLu mink lung epitheliai cells. The mean level of TGF-/f in TBPE (46 1 ± 31 5 pM; mean ± s.d.) was higher than in non-TBPE (217+12-3 pM) (/*<005). Although the level of interferon-gamma (IFN-/) in TBPE measured by FLISA was significantly higher than in non-TBPE. there was no significant difference in the levels of tumour necrosis factor-alpha (TNF-a) measured by ELISA between these two groups. Moreover, to elucidate localization of TGF"-// in tuberculous pleurisy, immunohistochemical studies of pleura, using the rabbit polyclonal antibody Ab39 against latent TGF-^1 binding protein (LTBP) were performed. Results revealed that LTBP was localized in immature fibrotic areas where infiltrations of T lymphocytes and maerophages were absent. Importantly, the major sources of LTBP in these areas were thought to be mesothclial cells and fibroblasts. LTBP was not found in granulomas and mature fibrotic areas. Our data suggest that JGF-fi in tuberculous pleurisy may play important roles for regression of granulomatous inflammation and pleural fibrosis for tissue repair.
This study was designed to assess whether the excessive secretion of transforming growth factor‐β1 (TGF‐β1) by Chinese hamster ovary (CHO) cells transfected with TGF‐β1 gene may be linked to the development of a metastatic phenotype. We observed large numbers of metastatic colonies in the lungs of nude mice inoculated with the transfected CHO cells. The tumors derived from these transfected cells demonstrated marked angiogenesis. We postulate that the overproduction of TGF‐β1 by these tumors may participate in the metastatic progression following establishment of angiogenesis at the primary tumor site.
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