The Experts below are selected from a list of 6540 Experts worldwide ranked by ideXlab platform
Sabine Werner - One of the best experts on this subject based on the ideXlab platform.
-
Keratinocyte Growth Factor: effects on Keratinocytes and mechanisms of action.
European Journal of Cell Biology, 2005Co-Authors: Ulrich Auf Dem Keller, Monika Krampert, Angelika Kümin, Susanne Braun, Sabine WernerAbstract:Summary Keratinocyte Growth Factor (KGF) is a potent and specific mitogen for different types of epithelial cells, and it can protect these cells from various insults. Due to these properties, it is of particular importance for the repair of injured epithelial tissues, and it is currently therapeutically explored for the treatment of radiation- and chemotherapy-induced mucosal epithelial damage in cancer patients. In this review we summarize the current knowledge on the role of KGF in tissue repair and cytoprotection, and we report on its mechanisms of action in Keratinocytes.
-
Keratinocyte Growth Factor a unique player in epithelial repair processes
Cytokine & Growth Factor Reviews, 1998Co-Authors: Sabine WernerAbstract:Abstract Keratinocyte Growth Factor (KGF) is a member of the rapidly growing fibroblast Growth Factor (FGF) family of mitogens. Whereas most FGFs influence proliferation and\or differentiation of various cell types, KGF seems to act specifically on epithelial cells. It has been demonstrated that KGF stimulates proliferation and migration of these cells, but it also affects differentiation processes. Finally, recent studies have demonstrated a protective function of this Growth Factor in vitro and in vivo . Due to these properties, KGF could play an important role in repair processes. Indeed a series of studies have provided insight into the expression and function of KGF in inflammation and repair of various tissues and organs, and a therapeutic potential of this Growth Factor has been demonstrated.
-
Keratinocyte Growth Factor is highly overexpressed in inflammatory bowel disease
American Journal of Pathology, 1996Co-Authors: Maria Brauchle, M Madlener, A Wagner, K Angermeyer, U M Lauer, P H Hofschneider, M Gregor, Sabine WernerAbstract:Recently we demonstrated an important function of Keratinocyte Growth Factor (KGF) in wound re-epithelialization. As KGF is mitogenic for various epithelial cells, we speculated about a role of KGF in epithelial repair processes of other organs as seen in a variety of inflammatory diseases. Here we demonstrate a strikingly increased expression of KGF in surgical specimens from patients suffering from Crohn's disease and ulcerative colitis. The levels of KGF expression strongly correlated with the degree of inflammation as assessed by histological analysis of adjacent tissue and expression analysis of the pro-inflammatory cytokine interleukin-1 beta. The highest levels of KGF mRNA and protein were found in mesenchymal cells of the lamina propria, particularly in highly inflamed areas. As the KGF receptor is expressed in intestinal epithelial cells, KGF seems to act in a paracrine manner to stimulate proliferation of these cells. These data suggest a crucial role of KGF in epithelial repair after injury caused by inflammatory processes.
Maria Rosaria Torrisi - One of the best experts on this subject based on the ideXlab platform.
-
Keratinocyte Growth Factor receptor (KGF-R) in cholesteatoma tissue
Acta Oto-laryngologica, 2009Co-Authors: Maurizio Barbara, Salvatore Raffa, Carmelo Murè, V. Manni, F. Ronchetti, Simonetta Monini, Maria Rosaria TorrisiAbstract:Conclusion. Distribution of the receptor for epidermal Growth Factor (EGF-R) and of the receptor for the Keratinocyte Growth Factor (KGF-R) in cholesteatoma was found to differ in analogy with other epithelial tissues and accordingly to epidermal differentiation and intensity of paracrine stimulation. Moreover, both EGF-R and KGF-R expression was increased, suggesting a fair correlation with aggressiveness and recurrence rate of this pathology. Objectives. To obtain information on the biological behaviour of cholesteatoma by assessing the expression and localization of EGF-R and KGF-R and correlating their tissue distribution with that of cytokeratins as a marker of differentiation. Materials and methods. Cholesteatoma tissue was taken during tympanoplasty surgery and processed for indirect immunofluorescence. Murine monoclonal antibodies were tested for the different Growth Factor receptors and pancytokeratins analysed. Fluorescence intensity signal was measured on randomly captured digital images, using...
-
Keratinocyte Growth Factor receptor ligands target the receptor to different intracellular pathways.
Traffic, 2007Co-Authors: Francesca Belleudi, Laura Leone, Valerio Nobili, Salvatore Raffa, Federica Francescangeli, Maddalena Maggio, Stefania Morrone, Cinzia Marchese, Maria Rosaria TorrisiAbstract:The Keratinocyte Growth Factor receptor (KGFR)/fibroblast Growth Factor receptor 2b is activated by high-affinity-specific interaction with two different ligands, Keratinocyte Growth Factor (KGF)/fibroblast Growth Factor (FGF)7 and FGF10/KGF2, which are characterized by an opposite requirement of heparan sulfate proteoglycans and heparin for binding to the receptor. We investigated here the possible different endocytic trafficking of KGFR, induced by the two ligands. Immunofluorescence and immunoelectron microscopy analysis showed that KGFR internalization triggered by either KGF or FGF10 occurs through clathrin-coated pits. Immunofluorescence confocal microscopy using endocytic markers as well as tumor susceptibility gene 101 (TSG101) silencing demonstrated that KGF drives KGFR to the degradative pathway, while FGF10 targets the receptor to the recycling endosomes. Biochemical analysis showed that KGFR is ubiquitinated and degraded after KGF treatment but not after FGF10 treatment, and that the alternative fate of KGFR might depend on the different ability of the receptor to phosphorylate the fibroblast Growth Factor receptor substrate 2 (FRS2) substrate and to recruit the ubiquitin ligase c-Cbl. The recycling endocytic pathway followed by KGFR upon FGF10 stimulation correlates with the higher mitogenic activity exerted by this ligand on epithelial cells compared with KGF, suggesting that the two ligands may play different functional roles through the regulation of the receptor endocytic transport.
-
Keratinocyte Growth Factor promotes melanosome transfer to Keratinocytes
Journal of Investigative Dermatology, 2005Co-Authors: Giorgia Cardinali, Maria Rosaria Torrisi, Simona Ceccarelli, Daniela Kovacs, Nicaela Aspite, Lavinia Vittoria Lotti, Mauro PicardoAbstract:Melanogenesis and melanosome transfer from the melanocytes to the neighboring Keratinocytes are induced by ultraviolet radiation and modulated by autocrine and paracrine Factors. Keratinocyte Growth Factor (KGF/fibroblast Growth Factor (FGF)7) is a paracrine mediator of human Keratinocyte Growth and differentiation. We evaluated the influence of KGF on melanosome transfer in co-cultures of Keratinocytes and melanocytes. Immunofluorescence analysis using anti-tyrosinase and anti-human cytokeratin antibodies, phagocytic assays using fluorescent latex beads, and ultrastructural analysis indicated that KGF is able to induce melanosome transfer acting only on the recipient Keratinocytes and as a consequence of a general role of KGF in the promotion of the phagocytic process. Inhibition of proteinase-activated receptor-2, to block the Rho-dependent phagocytic pathway, or of the Src family tyrosine kinases, to inhibit the Rac-dependent pathway, showed that KGF promotes phagocytosis through both mechanisms. Increased expression of the KGF receptor (KGFR) on the Keratinocytes by transfection led to increased phagocytosis of latex beads following KGF treatment, suggesting that the KGF effect is directly mediated by KGFR expression and activation. Moreover, confocal microscopic analysis revealed that KGFR localize in phagosomes during KGF-induced phagocytosis, suggesting a direct role of the receptor in regulating both the early steps of uptake and the intracellular traffic of the phagosomes.
-
The endocytic pathway followed by the Keratinocyte Growth Factor receptor
Histochemistry and Cell Biology, 2002Co-Authors: Francesca Belleudi, Cinzia Marchese, Luigi Frati, Mara Ceridono, Alessandro Capone, Annalucia Serafino, Mauro Picardo, Maria Rosaria TorrisiAbstract:Keratinocyte Growth Factor (KGF/FGF7) acts specifically on epithelial cells and regulates their proliferation and differentiation. It binds to and activates a receptor tyrosine kinase, the KGF receptor (KGFR), which is a splicing variant of the fibroblast Growth Factor receptor 2. The endocytic pathway followed by KGF and its receptor was analyzed here using immunofluorescence and confocal microscopy. After 10 min of internalization at 37°C, both KGF and its receptor were localized in early endosomes, and after 30–60 min of endocytosis ligand and receptor were seen to reach perinuclear late endosomes and not the recycling endosomal compartment. Parallel western blot analysis revealed that KGFRs were tyrosine phosphorylated both at early and late steps of internalization, suggesting that KGF and KGFR remain associated in active complexes through the endocytic pathway. Pulse-chase experiments showed that the internalized KGFRs underwent degradation detectable at 1 h of endocytosis at 37°C, indicating that KGFRs are functionally downregulated.
-
Receptor-mediated endocytosis of Keratinocyte Growth Factor
Journal of Cell Science, 1998Co-Authors: Cinzia Marchese, Francesca Belleudi, Patrizia Mancini, Alessandra Felici, Roberto Gradini, Tiziana Sansolini, Luigi Frati, Maria Rosaria TorrisiAbstract:Keratinocyte Growth Factor (KGF) is a fibroblast Growth Factor which acts specifically on epithelial cells, regulating their proliferation and differentiation. KGF elicits its activity through binding to and activation of KGF receptor, a splicing transcript variant of fibroblast Growth Factor receptor 2 (FGFR2). Here we analyzed the pathway of internalization of KGF and its receptor using several approaches, including the utilization in immunofluorescence and in immunoelectron microscopy of a functional KGF-HFc chimeric protein as a specific tool to follow the endocytosis of the Growth Factor and of its receptor. Western blot analysis with anti-FGFR2 and anti-phosphotyrosine antibodies, as well as parallel double immunofluorescence and confocal analysis of NIH3T3 KGFR transfectants treated with KGF at 4 degrees C, followed by incubations at 37 degrees C for different time points, showed that KGF induced endocytosis of tyrosine activated KGFRs. The use of KGF-HFc in immunofluorescence and in immunogold electron microscopy on KGFR transfectants, A253 epithelial tumor cells and human cultured Keratinocytes allowed us to follow the early steps of KGF internalization and revealed that this process occurred through clathrin-coated pits. A quantitative ELISA assay confirmed that KGF-HFc binding on the cell surface rapidly decreased because of internalization. Our results demonstrate that KGF is internalized by receptor-mediated endocytosis and illustrate the involvement of clathrin-coated pits in this process.
Hillard M Lazarus - One of the best experts on this subject based on the ideXlab platform.
-
recombinant human Keratinocyte Growth Factor successful treatment of severe refractory hemorrhagic cystitis after allogeneic hematopoietic cell transplantation
Bone Marrow Transplantation, 2014Co-Authors: S Bhaskaran, Rolla Abuarja, Ghada Abusin, Linda Cabral, Kristen Nagle, Sanjay P Ahuja, Rachel A Egler, Kenneth R Cooke, Hillard M LazarusAbstract:Recombinant human Keratinocyte Growth Factor: successful treatment of severe, refractory hemorrhagic cystitis after allogeneic hematopoietic cell transplantation
Jeffrey S Rubin - One of the best experts on this subject based on the ideXlab platform.
-
regulation of thymic epithelium by Keratinocyte Growth Factor
Blood, 2002Co-Authors: Matthew Erickson, Jeffrey S Rubin, Stanislaw Morkowski, Sophie M Lehar, Geoffrey O Gillard, Courtney Beers, James Dooley, Alexander Y Rudensky, Andrew G FarrAbstract:Here we demonstrate that Keratinocyte Growth Factor (KGF) and FGFR2IIIb signaling can affect development and function of thymic epithelium (TE) and that αβ-lineage thymocytes contribute to intrathymic levels of KGF. Thymocyte expression of KGF is developmentally regulated, being undetectable in CD3−4−8− thymocytes and expressed at highest levels by mature CD4 or CD8 thymocytes. Exposure of thymocyte-depleted fetal thymic lobes to KGF resulted in reduced thymic epithelial expression of class II major histocompatibility complex (MHC), invariant chain (Ii), and cathepsin L (CatL) molecules involved in thymocyte-positive selection and also stimulated expression of the cytokines interleukin 6 (IL-6) and thymic stromal-derived lymphopoietin (TSLP), while having little effect on IL-7 or stem cell Factor expression. Within intact fetal thymic organ culture (FTOC), exogenous KGF impairs the generation of CD4 thymocytes. Two lines of evidence point to responsiveness of the medullary TE compartment to KGF and FGFR2IIIb signaling. First, the medullary compartment is expanded in intact FTOC exposed to KGF in vitro. Second, in the RAG-deficient thymus, where the thymocytes do not express detectable levels of KGF message, the hypoplastic medullary TE compartment can be expanded by administration of recombinant KGF in vivo. This expansion is accompanied by restoration of the normal profile of medullary TE–associated chemokine expression in the RAG2−/−thymus. Collectively, these findings point to a role for KGF and FGFR signaling in the development and function of thymic epithelium.
-
Keratinocyte Growth Factor
Cell Biology International, 1995Co-Authors: Jeffrey S Rubin, Donald P Bottaro, Marcio Chedid, Toru Miki, Hyaegyeong Cheon, William G Taylor, Emma Fortney, Hiromi Sakata, Paul W Finch, William J LarochelleAbstract:Keratinocyte Growth Factor (KGF) is a member of the heparin-binding fibroblast Growth Factor family (FGF-7) with a distinctive pattern of target-cell specificity. Studies performed in cell culture suggested that KGF was mitogenically active only on epithelial cells, albeit from a variety of tissues. In contrast, KGF was produced solely by cells of mesenchymal origin, leading to the hypothesis that it might function as a paracrine mediator of mesenchymal-epithelial communication. Biochemical analysis and molecular cloning established that the KGF receptor (KGFR) was a tyrosine kinase isoform encoded by the fgfr-2 gene. Many detailed investigations of KGF and KGFR expression in whole tissue and cell lines largely substantiated the pattern initially perceived in vitro of mesenchymal and epithelial distribution, respectively. Moreover, functional assays in organ culture and in vivo and studies of KGF regulation by sex sterorid hormones reinforced the idea that KGF acts predominantly on epithelial cells to elicit a variety of responses including proliferation, migration and morphogenesis.
-
regulation of Keratinocyte Growth Factor gene expression by interleukin 1
Journal of Biological Chemistry, 1994Co-Authors: Marcio Chedid, Jeffrey S Rubin, Karl G Csaky, Stuart A AaronsonAbstract:Abstract Keratinocyte Growth Factor (KGF) is a stromally derived member of the fibroblast Growth Factor family (FGF7) with potent mitogenic activity on a variety of epithelial cells. To identify molecules that regulate the expression of this paracrine mediator of epithelial proliferation, we investigated the effects of various cytokines and Growth Factors on KGF production by fibroblasts. The proinflammatory cytokine interleukin 1 (IL1) strongly induced the expression of KGF RNA in fibroblasts from multiple sources. Platelet-derived Growth Factor BB, IL6, and transforming Growth Factor alpha caused a moderate elevation, while tumor necrosis Factor alpha and basic FGF did not alter the level of KGF RNA expression. The induction by IL1 of KGF transcript levels was time and dose dependent and specifically blocked by anti-IL1 antibodies. Nuclear run on experiments indicated that IL1 stimulated KGF gene transcription. Western blot analysis and Keratinocyte proliferation assays demonstrated a corresponding increase in mitogenically active KGF protein in conditioned medium obtained from IL1-treated fibroblasts. The stimulation of KGF expression by IL1 and other cytokines such as IL6, transforming Growth Factor alpha, and platelet-derived Growth Factor may provide a mechanism for KGF induction during inflammation that would support its proposed role as mediator of reepithelialization and wound healing.
-
Keratinocyte Growth Factor fgf 7 stimulates migration and plasminogen activator activity of normal human Keratinocytes
Journal of Investigative Dermatology, 1993Co-Authors: Ryoji Tsuboi, Jeffrey S Rubin, Chiyo Sato, Yoriyuki Kurita, Hideoki OgawaAbstract:Abstract Keratinocyte Growth Factor (KGF), a member of the fibroblast Growth Factor (FGF) family (and alternatively designated FGF-7), is a paracrine Growth Factor produced by mesenchymal cells and mitogenic specifically for epithelial cells. The potential effect of KGF on wound healing was assessed in vitro by measuring randomized migration and plasminogen activator (PA) activity of Keratinocytes in response to the Growth Factor. Incubation of normal human Keratinocytes with KGF in modified MCDB 153 medium significantly stimulated cell migration and PA activity compared with control (p in vitro results suggest that KGF may have an important role in stimulating reepithelialization during the process of wound repair.
Wolfgang Dorr - One of the best experts on this subject based on the ideXlab platform.
-
amelioration of acute oral mucositis by Keratinocyte Growth Factor fractionated irradiation
International Journal of Radiation Oncology Biology Physics, 2002Co-Authors: Wolfgang Dorr, Kathrin Spekl, Catherine L FarrellAbstract:Abstract Purpose: The aim of the present study was to quantify the protective efficacy of recombinant human Keratinocyte Growth Factor (rHuKGF) in oral mucosa. Methods and Materials: Mouse tongue mucosal ulceration was analyzed as the clinically relevant end point. Fractionated irradiation of the snout with 5 daily fractions of 3 Gy was followed by graded test doses, given to a test area of the lower tongue, on Day 7. rHuKGF was injected s.c. in daily doses of 5 mg/kg before radiotherapy, during radiotherapy, over the weekend break, or a combination. Moreover, single rHuKGF injections (5 or 15 mg/kg) were given on Day −1 or on Day 4. Results: In a single-dose control experiment, the ED50, i.e., the dose after which ulcer induction is expected in 50% of the mice, was 10.9 ± 0.7 Gy. Fractionated irradiation without Keratinocyte Growth Factor rendered an ED50 for test irradiation of 5.6 ± 3.7 Gy. Keratinocyte Growth Factor increased the ED50 values to 7.8 ± 3.3 Gy (Days −3 to −1, p = 0.01), 8.3 ± 1.6 Gy (Days −4 to −2, p = 0.0008), 10.5 ± 1.4 Gy (Days 0 to +2, p = 0.0002), 11.0 ± 0.5 Gy (Days 0 to +4, p = 0.002), 10.6 ± 1.4 Gy (Days +4 to +6, p = 0.0021), 10 ± 0.07 (Days −3 to +1, p = 0.0001) or 11.0 ± 0.02 (Days +4 to +8, p = 0.0001). This is equivalent to compensation of approximately 1.5 fractions of 3 Gy when rHuKGF is given before radiotherapy and 3–4 fractions in all other protocols by rHuKGF treatment. Single rHuKGF injections were similarly (5 mg/kg) or more (15 mg/kg) effective. Conclusions: In conclusion, these results indicate a marked increase in oral mucosal radiation tolerance by rHuKGF, which is most pronounced if the Growth Factor is applied during fractionated radiotherapy. The effect seems to be based on complex mechanisms, predominantly changes in both epithelial proliferation and differentiation processes.
-
Effect of Keratinocyte Growth Factor on Radiation Survival and Colony Size of Human Epidermal Keratinocytes In Vitro
Radiation Research, 2001Co-Authors: Dorota Słonina, Cordelia Hoinkis, Wolfgang DorrAbstract:Abstract Slonina, D., Hoinkis, C. and Dorr, W. Effect of Keratinocyte Growth Factor on Radiation Survival and Colony Size of Human Epidermal Keratinocytes In Vitro. Radiat. Res. 156, 761–766 (2001). Keratinocyte Growth Factor (FGF7, also known as KGF) ameliorates the radiation response of mouse oral mucosa and other epithelial tissues. However, the precise mechanisms remain unclear. The aim of the present study was to investigate the effect of FGF7 on the survival and colony size of normal human epidermal Keratinocytes in vitro. Primary neonatal Keratinocytes (HEKn) were irradiated with doses of 0 and 2 Gy of 200 kV X rays and incubated in the presence or absence of 100 ng/ml FGF7. The plating efficiency (PE) and surviving fraction (SF2) were determined using a clonogenic assay. In cell cultures without FGF7, the mean PE was 4.6 ± 0.2%. Irradiation with 2 Gy resulted in an SF2 of 51 ± 2%. In cell cultures with FGF7, the mean PE was identical, and a similar SF2 of 54 ± 1% was observed (P = 0.4). However, t...
-
modification of oral mucositis by Keratinocyte Growth Factor single radiation exposure
International Journal of Radiation Biology, 2001Co-Authors: Wolfgang Dorr, Kathrin Spekl, R Noack, Catherine L FarrellAbstract:Purpose : The aim was to quantify the effect of recombinant human Keratinocyte Growth Factor (rhKGF) on acute oral mucositis induced by a single radiation dose, simulating accidental radiation exposure. Material and methods : Tongue epithelium of the C3H/Neu mouse was irradiated with graded single doses of 25 kV X-rays to a 3x3 mm 2 area in the centre of the lower tongue surface. Acute mucosal ulceration, as a clinically relevant reaction, was used as the quantal endpoint for dose-response analyses by probit analysis. As a secondary endpoint the time-course, i.e. time to first diagnosis of ulcer (latent time) and individual ulcer duration, was analysed. KGF was applied before, after or in combination before and after radiation exposure. Results : Administration of KGF in all protocols resulted in a significant reduction of the incidence of oral mucosal ulceration, as illustrated by an increase in iso-effective dose from 10.9 to 24.9 Gy; the corresponding dose-modification Factors ranged between 1.7 and 2....
