|
| ||
|
|
||
CTGF Expression (ctgf + expression)
Selected AbstractsInhibition of connective tissue growth factor/CCN2 expression in human dermal fibroblasts by interleukin-1, and ,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2010D. Nowinski Abstract Connective tissue growth factor (CTGF/CCN2) is a matricellular protein induced by transforming growth factor (TGF)-, and intimately involved with tissue repair and overexpressed in various fibrotic conditions. We previously showed that keratinocytes in vitro downregulate TGF-,-induced expression of CTGF in fibroblasts by an interleukin (IL)-1 ,-dependent mechanism. Here, we investigated further the mechanisms of this downregulation by both IL-1, and ,. Human dermal fibroblasts and NIH 3T3 cells were treated with IL-1, or , in presence or absence of TGF-,1. IL-1 suppressed basal and TGF-,-induced CTGF mRNA and protein expression. IL-1, and , inhibited TGF-,-stimulated CTGF promoter activity, and the activity of a synthetic minimal promoter containing Smad 3-binding CAGA elements. Furthermore, IL-1, and , inhibited TGF-,-stimulated Smad 3 phosphorylation, possibly linked to an observed increase in Smad 7 mRNA expression. In addition, RNA interference suggested that TGF-, activated kinase1 (TAK1) is necessary for IL-1 inhibition of TGF-,-stimulated CTGF expression. These results add to the understanding of how the expression of CTGF in human dermal fibroblasts is regulated, which in turn may have implications for the pathogenesis of fibrotic conditions involving the skin. J. Cell. Biochem. 110: 1226,1233, 2010. Published 2010 Wiley-Liss, Inc. [source] Expression of connective tissue growth factor is in agreement with the expression of VEGF, VEGF-C, -D and associated with shorter survival in gastric cancerPATHOLOGY INTERNATIONAL, Issue 11 2007Luying Liu Connective tissue growth factor (CTGF) is believed to be a multifunctional signaling modulator involved in a wide variety of biological or pathological processes including carcinogenesis. The role of CTGF in gastric cancer (GC) has not been reported so far. In the present study the expression of CTGF, vascular endothelial growth factor (VEGF), VEGF-C and VEGF-D on immunohistochemistry in GC and the correlation between the expression of CTGF and VEGF, VEGF-C, VEGF-D were examined, along with the correlation between the expression of CTGF and clinicopathological parameters, as well as survival of the patients with GC. The expression of CTGF was significantly in agreement with expression of VEGF, VEGF-C and VEGF-D (, and P, respectively: 0.538, P < 0.001; 0.502, P < 0.001; 0.558, P < 0.001). High CTGF expression was significantly associated with lymph nodes metastasis (P = 0.038) and lower postoperative 5 year overall survival rates (23.9%) compared with those patients with low CTGF expression (48.4%, P = 0.0035). The present findings suggest that CTGF is a useful prognostic marker for GC. High CTGF expression is associated with the risk of lymph nodes metastasis and a poor survival time in GC. [source] Connective Tissue Growth Factor Promotes Fibrosis Downstream of TGF, and IL-6 in Chronic Cardiac Allograft RejectionAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2010A. J. Booth Cardiac transplantation is an effective treatment for multiple types of heart failure refractive to therapy. Although immunosuppressive therapeutics have increased survival rates within the first year posttransplant, chronic rejection (CR) remains a significant barrier to long-term graft survival. Indicators of CR include patchy interstitial fibrosis, vascular occlusion and progressive loss of graft function. Multiple factors have been implicated in the onset and progression of CR, including TGF,, IL-6 and connective tissue growth factor (CTGF). While associated with CR, the role of CTGF in CR and the factors necessary for CTGF induction in vivo are not understood. To this end, we utilized forced expression and neutralizing antibody approaches. Transduction of allografts with CTGF significantly increased fibrotic tissue development, though not to levels observed with TGF, transduction. Further, intragraft CTGF expression was inhibited by IL-6 neutralization whereas TGF, expression remained unchanged, indicating that IL-6 effects may potentiate TGF,-mediated induction of CTGF. Finally, neutralizing CTGF significantly reduced graft fibrosis without reducing TGF, and IL-6 expression levels. These findings indicate that CTGF functions as a downstream mediator of fibrosis in CR, and that CTGF neutralization may ameliorate fibrosis and hypertrophy associated with CR. [source] Regulation of CCN2/Connective tissue growth factor expression in the nucleus pulposus of the intervertebral disc: Role of Smad and activator protein 1 signalingARTHRITIS & RHEUMATISM, Issue 7 2010Cassie M. Tran Objective To investigate transforming growth factor , (TGF,) regulation of connective tissue growth factor (CTGF) expression in cells of the nucleus pulposus of rats, mice, and humans. Methods Real-time reverse transcription,polymerase chain reaction and Western blot analyses were used to measure CTGF expression in the nucleus pulposus. Transfections were used to measure the effects of Smads 2, 3, and 7 and activator protein 1 (AP-1) on TGF,-mediated CTGF promoter activity. Results CTGF expression was lower in neonatal rat discs than in skeletally mature rat discs. An increase in CTGF expression and promoter activity was observed in rat nucleus pulposus cells after TGF, treatment. Deletion analysis indicated that promoter constructs lacking Smad and AP-1 motifs were unresponsive to treatment. Analysis showed that full-length Smad3 and the Smad3 MH-2 domain alone increased CTGF activity. Further evidence of Smad3 and AP-1 involvement was seen when DN-Smad3, SiRNA-Smad3, Smad7, and DN-AP-1 suppressed TGF,-mediated activation of the CTGF promoter. When either Smad3 or AP-1 sites were mutated, CTGF promoter induction by TGF, was suppressed. We also observed a decrease in the expression of CTGF in discs from Smad3-null mice as compared with those from wild-type mice. Analysis of human nucleus pulposus samples indicated a trend toward increasing CTGF and TGF, expression in the degenerated state. Conclusion TGF,, through Smad3 and AP-1, serves as a positive regulator of CTGF expression in the nucleus pulposus. We propose that CTGF is a part of the limited reparative response of the degenerated disc. [source] Pivotal role of connective tissue growth factor in lung fibrosis: MAPK-dependent transcriptional activation of type I collagenARTHRITIS & RHEUMATISM, Issue 7 2009Markella Ponticos Objective Connective tissue growth factor (CTGF; CCN2) is overexpressed in systemic sclerosis (SSc) and has been hypothesized to be a key mediator of the pulmonary fibrosis frequently observed in this disease. CTGF is induced by transforming growth factor , (TGF,) and is a mediator of some profibrotic effects of TGF, in vitro. This study was undertaken to investigate the role of CTGF in enhanced expression of type I collagen in bleomycin-induced lung fibrosis, and to delineate the mechanisms of action underlying the effects of CTGF on Col1a2 (collagen gene type I ,2) in this mouse model and in human pulmonary fibroblasts. Methods Transgenic mice that were carrying luciferase and ,-galactosidase reporter genes driven by the Col1a2 enhancer/promoter and the CTGF promoter, respectively, were injected with bleomycin to induce lung fibrosis (or saline as control), and the extracted pulmonary fibroblasts were incubated with CTGF blocking agents. In vitro, transient transfection, promoter/reporter constructs, and electrophoretic mobility shift assays were used to determine the mechanisms of action of CTGF in pulmonary fibroblasts. Results In the mouse lung tissue, CTGF expression and promoter activity peaked 1 week after bleomycin challenge, whereas type I collagen expression and Col1a2 promoter activity peaked 2 weeks postchallenge. Fibroblasts isolated from the mouse lungs 14 days after bleomycin treatment retained a profibrotic expression pattern, characterized by greatly elevated levels of type I collagen and CTGF protein and increased promoter activity. In vitro, inhibition of CTGF by specific small interfering RNA and neutralizing antibodies reduced the collagen protein expression and Col1a2 promoter activity. Moreover, in vivo, anti-CTGF antibodies applied after bleomycin challenge significantly reduced the Col1a2 promoter activity by ,25%. The enhanced Col1a2 promoter activity in fibroblasts from bleomycin-treated lungs was partly dependent on Smad signaling, whereas CTGF acted on the Col1a2 promoter by a mechanism that was independent of the Smad binding site, but was, instead, dependent on the ERK-1/2 and JNK MAPK pathways. The CTGF effect was mapped to the proximal promoter region surrounding the inverted CCAAT box, possibly involving CREB and c-Jun. In human lung fibroblasts, the human COL1A2 promoter responded in a similar manner, and the mechanisms of action also involved ERK-1/2 and JNK signaling. Conclusion Our results clearly define a direct profibrotic effect of CTGF and demonstrate its contribution to lung fibrosis through transcriptional activation of Col1a2. Blocking strategies revealed the signaling mechanisms involved. These findings show CTGF to be a rational target for therapy in fibrotic diseases such as SSc. [source] High expression of connective tissue growth factor in pre-B acute lymphoblastic leukaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2007Joanne M. Boag Summary In recent years microarrays have been used extensively to characterize gene expression in acute lymphoblastic leukaemia (ALL). Few studies, however, have analysed normal haematopoietic cell populations to identify altered gene expression in ALL. We used oligonucleotide microarrays to compare the gene expression profile of paediatric precursor-B (pre-B) ALL specimens with two control cell populations, normal CD34+ and CD19+IgM, cells, to focus on genes linked to leukemogenesis. A set of eight genes was identified with a ninefold higher average expression in ALL specimens compared with control cells. All of these genes were significantly deregulated in an independent cohort of 101 ALL specimens. One gene, connective tissue growth factor (CTGF, also known as CCN2), had exceptionally high expression, which was confirmed in three independent leukaemia studies. Further analysis of CTGF expression in ALL revealed exclusive expression in B-lineage, not T-lineage, ALL. Within B-lineage ALL approximately 75% of specimens were consistently positive for CTGF expression, however, specimens containing the E2A-PBX1 translocation showed low or no expression. Protein studies using Western blot analysis demonstrated the presence of CTGF in ALL cell-conditioned media. These findings indicate that CTGF is secreted by pre-B ALL cells and may play a role in the pathophysiology of this disease. [source] Curcumin: potential for hepatic fibrosis therapy?BRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2008M A O'Connell The beneficial antioxidative, anti-inflammatory and antitumorigenic effects of curcumin have been well documented in relation to cancer and other chronic diseases. Recent evidence suggests that it may be of therapeutic interest in chronic liver disease. Hepatic fibrosis (scarring) occurs in advanced liver disease, where normal hepatic tissue is replaced with collagen-rich extracellular matrix and, if left untreated, results in cirrhosis. Curcumin inhibits liver cirrhosis in a rodent model and exerts multiple biological effects in hepatic stellate cells (HSCs), which play a central role in the pathogenesis of hepatic fibrosis. In response to liver injury, these cells proliferate producing pro-inflammatory mediators and extracellular matrix. Curcumin induces apoptosis and suppresses proliferation in HSCs. In addition, it inhibits extracellular matrix formation by enhancing HSC matrix metalloproteinase expression via PPAR, and suppressing connective tissue growth factor (CTGF) expression. In this issue, Chen and co-workers propose that curcumin suppresses CTGF expression in HSC by inhibiting ERK and NF-,B activation. These studies suggest that curcumin modulates several intracellular signalling pathways in HSC and may be of future interest in hepatic fibrosis therapy. British Journal of Pharmacology (2008) 153, 403,405; doi:10.1038/sj.bjp.0707580; published online 26 November 2007 [source] Expression and regulation of connective tissue growth factor by transforming growth factor , and tumour necrosis factor , in fibroblasts isolated from strictures in patients with Crohn's diseaseBRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 10 2006D. Beddy Background: Connective tissue growth factor (CTGF) stimulates fibroblast proliferation and extracellular matrix production. Fibroblasts may initiate stricture formation in Crohn's disease through overexpression of CTGF. Stricturing that occurs in patients with Crohn's disease after treatment with anti-tumour necrosis factor (TNF) , may be due to dysregulation of CTGF homeostasis. The aim of this study was to examine CTGF expression and regulation in fibroblasts isolated from patients with Crohn's disease. Methods: Fibroblasts were isolated by a primary explant technique from serosal biopsies of strictured segments of bowel in eight patients undergoing resection for Crohn's disease and from normal colon in seven patients having resection for benign or malignant colorectal disease. Cells were stimulated with transforming growth factor (TGF) , and TNF-,. CTGF protein and mRNA expression were measured by western blotting and real-time polymerase chain reaction respectively. Results: Mean(s.d.) CTGF protein expression in strictured Crohn's fibroblasts was higher than that in normal fibroblasts (56·5(9·7) versus 17·0(10·0) respectively; P = 0·011). In normal and strictured Crohn's fibroblasts, culture with TGF-, increased CTGF protein and mRNA expression. Co-culture of normal fibroblasts with TNF-, suppressed TGF-,-stimulated CTGF expression. Conclusion: Increased expression of CTGF in strictured Crohn's fibroblasts underlies its role in fibrosis. TNF-, suppresses fibrosis by downregulating fibroblast CTGF expression, an effect that may be lost following anti-TNF-, treatment, thereby promoting stricture formation. Copyright © 2006 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] | ||||||||||