Keratinocyte Growth Factor Receptor mRNA Research Articles

Keratinocyte growth factor is an endogenous stimulant of rabbit gastric epithelial cell proliferation and migration in primary culture.

Mesenchymal-epithelial interactions are important in the gastric mucosal repair. However, specific factors responsible for such interactions have not been established. In the present study, keratinocyte growth factor (KGF) significantly stimulated proliferation of gastric epithelial cells dose dependently and synergistically with hepatocyte growth factor (HGF), epidermal growth factor (EGF) and insulin. Restitution of gastric epithelial monolayers was also assessed, using a round wound restitution model. Keratinocyte growth factor facilitated the restitution of gastric epithelial cells significantly but did not have any effects on gastric fibroblasts. Keratinocyte growth factor receptor mRNA was expressed by gastric epithelial cells, indicating that these effects were elicited by the specific receptor mediated pathway. Northern blot analysis revealed the expression of KGF mRNA in gastric fibroblasts but not in gastric epithelial cells, indicating the production of KGF. These results suggest that KGF might be involved in gastric mucosal repair, through mesenchymal-epithelial interaction.

Suppression of Keratinocyte Growth Factor Expression by Glucocorticoids In Vitro and During Wound Healing

We have recently demonstrated an important function of keratinocyte growth factor (KGF) in morphogenesis of epithelium and wound re-epithelialization. Furthermore, abnormalities in KGF expression or responsiveness are associated with wound-healing defects. In this study we have analyzed the regulation of KGF expression during wound repair in glucocorticoid-treated mice that are characterized by severe wound healing abnormalities. Induction of KGF mRNA expression after skin injury was significantly reduced in these mice, whereas KGF receptor mRNA levels were only affected to a minor extent by glucocorticoid treatment. The reduced KGF expression during wound healing in steroid-treated animals is at least partially due to a direct effect of glucocorticoids on the KGF expressing mesenchymal cells, because treatment of cultured fibroblasts with dexamethasone reduced KGF mRNA levels in a time- and concentration-dependent manner. The inhibitory effect of glucocorticoids on KGF expression was compensated for by high levels of serum growth factors or pro-inflammatory cytokines, demonstrating that KGF expression is subject to positive and negative regulation. Thus it seems likely that a fine balance of various KGF-regulating factors is important for normal wound healing.

Keratinocyte Growth Factor and Receptor mRNA Expression in Benign and Malignant Human Prostate

We have examined whether keratinocyte growth factor (KGF) and its receptor are expressed in normal, fetal, and prostate cancer cells since KGF may play a role in the growth of adenocarcinomas. In situ hybridization studies with digoxigenin-labeled oligonucleotides (anti-sense and sense controls) were employed to examine KGF and KGF receptor mRNA expression in prostate cancer. We found that the KGF and KGF receptor genes were faintly expressed in the stromal and epithelial cells, respectively, in both fetal ( n = 6) and normal adult prostate ( n = 6) tissues examined, In 10 benign prostatic hyperplasias (BPH), and in low- and high-grade prostatic carcinoma (32 total), both the KGF gene and the receptor mRNA were expressed in the glandular epithelial cells. KGF was also expressed by the stromal cells in BPH and low-grade carcinoma. Computer assisted system analysis indicated that the intensity of epithelial labeling by both probes was increased in high Gleason score carcinomas (>8) and in metastatic nodules, We interpret the data to mean that the paracrine loop in normal prostate may be replaced by an autocrine loop in BPH and adenocarcinomas.

Expression of mRNA for keratinocyte growth factor and its receptor in human endometrium.

The aim of the present study was to evaluate the expression of mRNA for the keratinocyte growth factor and the keratinocyte growth factor receptor in human endometrium at different stages of the menstrual cycle. The role of estrogen and progesterone in regulating the expression of the mRNAs encoding keratinocyte growth factor and its receptor was further examined by studying the effect of continuous progestin (endometrium exposed to levonorgestrel releasing intrauterine contraceptive device), and continuous estrogen (endometrium hyperplasia) on the endometrium. The expression of mRNA in endometrial samples was evaluated using reverse transcriptase polymerase chain reaction. The expression of KGF mRNA was found to vary during the menstrual cycle, with the highest levels in the progesterone-dominated late-secretory stage endometrium. Keratinocyte growth factor mRNA expression was low in both the endometrium that had been under the influence of continuous progestin (atrophic endometrium) and continuous estrogen (hyperplastic endometrium). The highest level of keratinocyte growth factor receptor mRNA expression was seen in late-proliferative stage of the menstrual cycle and in hyperplasia when the estrogen exposure to endometrium is high. A low receptor mRNA level was found in endometrium exposed to continuous progestin. The results suggest that keratinocyte growth factor mRNA expression is progesterone dependent, whereas keratinocyte growth factor receptor mRNA expression seems to be more estrogen than progesterone dependent.

Pattern of keratinocyte growth factor and keratinocyte growth factor receptor expression during mouse fetal development suggests a role in mediating morphogenetic mesenchymal-epithelial interactions.

Mesenchymal cells are required for the induction of epithelial development during mammalian organogenesis. Keratinocyte growth factor (KGF) is a mesenchymally derived mitogen with specific activity for epithelial cells, suggesting that it may play a role in mediating these interactions. To further evaluate this hypothesis, in situ hybridization was used to examine the spatial distribution of KGF and KGF receptor (KGFR) transcripts during organogenesis and limb formation in mouse embryos (days 14.5 through 16.5). To facilitate this aim, mouse KGF cDNA clones were isolated. There was extensive identity between the deduced mouse KGF protein sequence and that of its human and rat cognates, indicating that this gene has been highly conserved during mammalian evolution. In addition, mouse KGF protein was purified from fibroblasts and demonstrated to be structurally and functionally similar to human KGF protein. For organs within the integumental, respiratory, gastrointestinal, and urogenital systems, whose development is dependent upon mesenchymal-epithelial interactions, KGF mRNA was detected in mesenchymal cells, while epithelial cells expressed transcripts for the KGFR, KGF and KGFR mRNA was also expressed in certain other tissues such as perichondrium, cartilage of developing bones, developing skeletal muscle, and visceral smooth muscle whose development is not regulated by mesenchymal-epithelial interactions. KGF expression was also detected in tissues isolated from human embryos, suggesting similar functions for KGF in human development. Taken together, our results suggest that KGF plays an important role in mediating mesenchymal-epithelial interactions during organogenesis, but may also have other developmental functions in tissues not governed by such interactions.

Paracrine Role of Keratinocyte Growth Factor in Rabbit Corneal Epithelial Cell Growth

Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family, is expressed in stromal fibroblasts and acts specifically on cells of epithelial origin as a paracrine mediator. In this study, we examined KGF and KGF receptor (KGF-R) mRNA expression in rabbit corneal epithelial cells and keratocytes, using a reverse transcription polymerase chain reaction (RT-PCR) method. We also examined the effects of KGF on the proliferation of rabbit corneal cells in vitro. mRNA from cultured rabbit skin fibroblasts, conjunctival fibroblasts, corneaI epithelial cells and keratocytes was first reverse-transcribed, and then amplified by PCR using primers specific for KGF and KGF-R. KGF mRNA was expressed in skin fibroblasts, conjunctival fibroblasts and keratocytes, but not in corneal epithelial cells. In contrast, KGF receptor mRNA was expressed in corneal epithelial cells, but not in skin fibroblasts, conjunctival fibroblasts or keratocytes. The results of Southern hybridization experiments of PCR products also showed that KGF mRNA was expressed in skin fibroblasts, conjunctival fibroblasts and keratocytes, whereas KGF receptor mRNA was expressed in corneal epithelial cells. Nucleotide sequencing of the PCR products revealed that their sequences were identical to the expected nucleotide sequences. Using the methylene blue method, we found that KGF enhanced the growth of cultured rabbit corneal epithelial cells, but not keratocytes, at a concentration of 0·01 to 100 ng ml -1. Furthermore, KGF also augmented 3H-thymidine incorporation into the corneal epithelial cells. These results suggest that KGF is a paracrine mediator of the proliferation of corneal epithelial cells as well as of keratinocytes in the skin.

Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo.

Keratinocyte growth factor (KGF) administered as a single intratracheal injection causes a prominent dose-dependent proliferation of type II alveolar epithelial cells in the lungs of adult rats. The increase in mitotically active alveolar cells histologically appears as a micropapillary epithelial cell hyperplasia after 2 d and peaks after 3 d in the form of monolayers of cuboidal epithelial cells lining alveolar septae. Proliferating cell nuclear antigen immunohistochemistry confirmed the profound proliferative response induced by KGF. The hyperplastic alveolar lining cells contain immunoreactive surfactant protein B and are ultrastructurally noted to contain lamellar inclusions characteristic of surfactant-producing type II pneumocytes. Mild focal bronchiolar epithelial hyperplasia is noted but is much less striking than the proliferation of type II pneumocytes. Large airways are unaffected by KGF. Daily intravenous injection of KGF is also able to cause pneumocyte proliferation. The normal adult rat lung constitutively expresses both KGF and KGF receptor mRNA, suggesting that endogenous KGF may be implicated in the paracrine regulation of the growth of pneumocytes. In conclusion, KGF rapidly and specifically induces proliferation and differentiation of type II pneumocytes in the normal adult lung.

Differential expression of keratinocyte growth factor and its receptor in the human uterus

The expression of mRNAs for keratinocyte growth factor (KGF) (also called FGF-7) and its receptor was evaluated in normal human endometrium and myometrium as well as in myoma and in endometrial adenocarcinoma cell lines using reverse transcriptase polymerase chain reaction. Both KGF and its receptor mRNA are expressed in the human endometrium throughout the menstrual cycle, whereas fibroblast growth factor receptor 2 (FGFR-2) mRNA expression is low in this tissue. In endometrial stromal cell enriched preparations KGF mRNA dominates with little expression of KGF receptor (KGFR) and FGFR-2, whereas in the epithelial cell-enriched fraction the KGFR mRNA dominates. Human myometrium and myoma express mRNA for KGF, but not for KGFR. FGFR-2 is expressed in both myometrial and myoma tissues. None of the five endometrial adenocarcinoma cell lines studied expressed KGF mRNA, whereas all cell lines expressed mRNA for either KGFR or FGFR-2 or for both receptors. The results show a selective expression of KGFR and the closely related FGFR-2 in the human uterus with the former being expressed in the endometrium and the latter predominantly in the adjacent myometrium. In the endometrial tissue, selective expression of KGF in stromal cells and KGFR in epithelial cells supports the paracrine function of KGF in epithelial tissue.