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PubMed1977

Effects of glucocorticosteroids on primary human skin fibroblasts. I. Inhibition of the proliferation of cultured primary human skin and mouse L929 fibroblasts.

Various glucocorticosteroids were added to logarithmically growing cultures of primary human skin fibroblasts and of mouse L929 fibroblasts. These steroids inhibited proliferation of the human fibroblasts at concentrations which fall in a range expected to occur during the topical treatment of skin disorders. In terms of the concentrations required for the inhibition hydrocortisone was least and clobetasol-17-propionate most effective. All other steroids studied (hydrocortisone-17-butyrate, triamcinolone acetonide, betamethasone-17-valerate and hydrocortisone-21-acetate) showed medium effectiveness. Fluorination as such may not enhance the inhibitory effect. The inhibition was independent of the source (baby foreskin or adult arm skin) and passage number (7th to 13th or 15th and 16th passage, respectively) of the cells. The possible relationship between the inhibition of cell proliferation by such steroids and their therapeutic effect in psoriasis and their atrophic side effects is discussed. Mouse L929 fibroblasts were affected at 10(3)--10(4)-fold lower steroid concentrations and the range of the effective concentrations was 10(4)--10(5) times as wide as that for the primary human skin fibroblasts. It was concluded that these mouse fibroblasts are a poor model system for the study of in vivo effects of glucocorticosteroids in man.

Administration, Topical↗
PubMed1992

Description of a selection method highly cytotoxic for cystinotic fibroblasts but not normal human fibroblasts.

Nephropathic cystinosis is an inherited disorder characterized by a high intralysosomal accumulation of cystine due to a defect in lysosomal cystine transport. Cystine can be specifically loaded into the lysosomal compartment of intact cells by incubating cells with cystine dimethyl ester (CDME). We have applied this methyl ester loading technique to develop a selection method that is highly cytotoxic for cystinotic fibroblasts but not normal human fibroblasts and that is based on the inherent differences in lysosomal cystine transport activity of normal and cystinotic fibroblasts. Thus, only 0-0.03% of fetal cystinotic fibroblasts survive exposure to 2 mM CDME for 20 min whereas 70-80% of normal fetal fibroblasts survive these same conditions. Following transfection of cystinotic fibroblasts with normal human genomic DNA or cDNA, this CDME selection method can be used to select for those cells that have been transformed to the normal phenotype and thus aid in the identification of the gene coding for the lysosomal cystine transport protein.

Biological Transport↗
PubMed1989

Synergy of interleukin 1 (IL-1) with arachidonic acid and A23187 in stimulating PGE synthesis in human fibroblasts: IL-1 stimulates fibroblast cyclooxygenase.

The stimulation of prostaglandin E (PGE) synthesis by interleukin 1 (IL-1) has important physiologic effects in many target tissues. The mechanism(s) whereby IL-1 stimulates PGE synthesis is not well understood. Two alternative mechanisms have been postulated: hydrolysis of membrane phospholipid with release of arachidonic acid substrate and induction of cyclooxygenase activity. We examined these mechanisms in IL-1 stimulation of human dermal fibroblast PGE synthesis. IL-1 failed to induce release of previously incorporated radiolabeled arachidonic acid from fibroblasts under conditions where there was a 30-fold or greater stimulation of PGE synthesis. The calcium ionophore, A23187, gave much less stimulation of PGE synthesis while inducing 30-100% release of incorporated [14C]arachidonic acid. There was marked synergy between IL-1 and agents which increased availability of arachidonic acid. For example, the combination of IL-1 and A23187, used at concentrations where neither agent alone stimulated PGE synthesis, increased PGE synthesis from 3.1 to 22.5 ng/ml; similar synergy was seen between IL-1 and exogenous arachidonic acid. To examine a possible effect of IL-1 on cyclooxygenase synthesis, fibroblast cyclooxygenase was measured by radioimmunoassay. Following treatment with IL-1, fibroblasts demonstrated a two- to threefold increase in content of immunoreactive cyclooxygenase. These results suggest that IL-1 increases fibroblast PGE synthesis by a mechanism(s) other than making available increased membrane arachidonic acid, and that at least part of its effect may be mediated by induction of cyclooxygenase. Furthermore, the effect of IL-1 on fibroblast PGE synthesis is markedly potentiated by agents which increase available substrate.

Arachidonic Acid↗
PubMed1991

Monocytic origin of fibroblasts: spontaneous transformation of blood monocytes into neo-fibroblastic structures in osteomyelosclerosis and Engelmann's disease.

We describe here two pathological situations, osteomyelosclerosis and Engelmann's disease, in which HLA-DR blood monocytes modulate to the fibroblastic class, in long-term culture. Monocytes/macrophages were identified by immunofluorescence, using monoclonal antibodies against surface markers (Leu M3, CD 68, and HLA-DR) and the neo-fibroblasts by electron microscopy and immunofluorescence using monoclonal antibodies against a cytoplasmic enzyme specifically involved in the synthesis of collagen (5B5). Macrophages makers were found on the neo-fibroblasts, whereas HLA-DR macrophages expressed the cytoplasmic marker 5B5. Since osteoblasts are classically derived from fibroblasts, the significance of the in vitro differentiation of monocytes/macrophages into fibroblasts to the in vivo mechanism leading to excessive osteoblastic proliferation in both osteomyelosclerosis and Engelmann's disease, is discussed. The possible involvement of this pathway leading from monocytes to fibroblasts and osteoblasts in the normal process of bone modeling and remodeling in questioned.

Camurati-Engelmann Syndrome↗
PubMed1972

Gene dosage dependence of pigment synthesis in melanoma x fibroblast hybrids (hamster cells-mouse fibroblast-DOPA-oxidase-irradiation).

Hybrids between Syrian hamster melanoma cells and mouse fibroblasts, containing one genome (1s) of each parent, produce neither melanin nor DOPA-oxidase ("extinction"). Attempts to induce loss of the fibroblast chromosomes by irradiation of the fibroblasts before fusion with melanoma cells resulted in the formation of colonies comprising pigmented hybrid cells, which contained 2s melanoma and 1s fibroblast chromosome-complements suggesting that extinction or re-expression of melanogenesis is a function of genic balance. This interpretation was confirmed by crosses between 2s melanoma cells with unirradiated 1s fibroblasts, which produced both pigmented and unpigmented hybrids. No correlation has thus far been established between karyotype and phenotype of the hybrid cells, but analysis of the karyological data suggests that the fibroblast chromosomes responsible for extinction cannot be numerous.

Animals↗
PubMed2002

Irradiated homozygous TGF-beta1 knockout fibroblasts show enhanced clonogenic survival as compared with TGF-beta1 wild-type fibroblasts.

PURPOSE: To study the role of transforming growth factor beta1 (TGF-beta1) on cellular radiation sensitivity by analysing mouse lung fibroblasts of different TGF-beta1 genotypes. MATERIALS AND METHODS: Heterozygous TGF-beta1 knock-out mice were mated to produce offspring of different TGF-beta1 genotypes as confirmed by PCR-genotyping. Primary lung fibroblast populations were established from new-born animals of specific genotypes (TGF-beta1(+/+), TGF-beta1(+/-), TGF-beta1(-/-)). Production of TGF-beta1 was tested by ELISA. TGF-beta1 receptor-II mRNA expression was analysed by RT-PCR. Colony formation of untreated, TGF-beta1-treated and/or irradiated primary lung fibroblasts was determined under different medium conditions. RESULTS: Plating efficiencies under different medium conditions were independent of TGF-beta1 genotype. Production of TGF-beta1 correlated with the genotype: heterozygous TGF-beta1 knock-out fibroblasts (TGF-beta1(+/-)) produced 60-65% of wild-type (TGF-beta1(+/+) cells). As expected, homozygous TGF-beta1 knock-out fibroblasts (TGF-beta1(-/-)) did not produce TGF-beta1. Radiation exposure significantly enhanced TGF-beta1 production in TGF-beta1(+/+) cells by a factor of 2. No such stimulation was observed in TGF-beta1(+/-) cells. TGF-beta1(+/-) and especially TGF-beta1(-/-) cells were significantly more radioresistant than TGF-beta1(+/+) cells. TGF-beta1 treatment significantly reduced clonogenic survival for both TGF-beta1(+/+) and TGF-beta1(-/-) cells. TGF-beta1 treatment of TGF-beta1(-/-) cells resulted in an enhancement of radiation sensitivity. CONCLUSION: The data are the first direct evidence that TGF-beta1 is a major autocrine regulator of intrinsic radiation sensitivity of mouse lung fibroblasts.

Activin Receptors, Type I↗
PubMed2026

Local gene editing of fibroblasts in tumors reveals a new cancer-associated fibroblast state.

Fibroblasts play critical roles in regulating cellular relationships during tissue homeostasis, immunity, and tumor biology at multiple sites. However, tools to perturb fibroblasts at just one site in vivo are limited, restricting our understanding of how these cellular relationships act locally. We optimized local gene editing of fibroblasts in mouse tumor models to investigate how fibroblast perturbations affect the tumor microenvironment (TME). By knocking out receptors Osmr, Tgfbr2, or Il1r1 on cancer-associated fibroblasts (CAFs), we uncover that TGFBR2 signaling loss induces the emergence of a new Col18a1hi CAF cell state that is associated with worse survival in pancreatic cancer patients. Combinatorial gene KOs in CAFs reveals a circuit where these Col18a1hi CAFs reshape the TME by recruiting Siglec-Fhi neutrophils via Cxcl5 expression, and where this Col18a1hi CAF cell state is dependent on TNFR1 and canonical Wnt signaling. Together, a fast, affordable, and modular engineering method is demonstrated, allowing discovery of modified fibroblast identities and local intercellular relationships in the TME.

Animals↗
PubMed1998

Collagenase-3 induction in rat lung fibroblasts requires the combined effects of tumor necrosis factor-alpha and 12-lipoxygenase metabolites: a model of macrophage-induced, fibroblast-driven extracellular matrix remodeling during inflammatory lung injury.

The mechanisms responsible for the induction of matrix-degrading proteases during lung injury are ill defined. Macrophage-derived mediators are believed to play a role in regulating synthesis and turnover of extracellular matrix at sites of inflammation. We find a localized increase in the expression of the rat interstitial collagenase (MMP-13; collagenase-3) gene from fibroblastic cells directly adjacent to macrophages within silicotic rat lung granulomas. Conditioned medium from macrophages isolated from silicotic rat lungs was found to induce rat lung fibroblast interstitial collagenase gene expression. Conditioned medium from primary rat lung macrophages or J774 monocytic cells activated by particulates in vitro also induced interstitial collagenase gene expression. Tumor necrosis factor-alpha (TNF-alpha) alone did not induce interstitial collagenase expression in rat lung fibroblasts but did in rat skin fibroblasts, revealing tissue specificity in the regulation of this gene. The activity of the conditioned medium was found to be dependent on the combined effects of TNF-alpha and 12-lipoxygenase-derived arachidonic acid metabolites. The fibroblast response to this conditioned medium was dependent on de novo protein synthesis and involved the induction of nuclear activator protein-1 activity. These data reveal a novel requirement for macrophage-derived 12-lipoxygenase metabolites in lung fibroblast MMP induction and provide a mechanism for the induction of resident cell MMP gene expression during inflammatory lung processes.

Animals↗
PubMed1997

Exposure of fibroblasts derived from keloid patients to low-energy electromagnetic fields: preferential inhibition of cell proliferation, collagen synthesis, and transforming growth factor beta expression in keloid fibroblasts in vitro.

We studied the effects of electromagnetic fields (EMFs) on cell proliferation and collagen synthesis in both normal and keloid fibroblasts in vitro. Treatment of keloid fibroblasts with 60-Hz EMFs for 10 days resulted in the inhibition of cell proliferation, whereas no significant change in cell proliferation of normal fibroblasts was observed. EMFs inhibited collagen synthesis in keloid fibroblasts but not in normal fibroblasts without altering the ratio of type III to type I collagen, indicating that EMFs inhibit type I and type III collagen synthesis to the same extent. EMFs also decreased the expression of transforming growth factor beta (TGF-beta) in keloid fibroblasts. These results suggest that EMFs may have a useful therapeutic potential for the treatment of keloid.

Adolescent↗
PubMed2000

Differential expression of receptor tyrosine kinases and Shc in fetal and adult rat fibroblasts: toward defining scarless versus scarring fibroblast phenotypes.

The remarkable ability of the fetus to heal early gestation skin wounds without scarring remains poorly understood. Taking advantage of recent advances in signal transduction, the tyrosine phosphorylation patterns of fetal rat fibroblasts, representing the scarless cutaneous repair phenotype, and adult rat fibroblasts, representing scarforming phenotype, were examined whether there were inherent differences in cellular signaling. Specifically, correlation of the phosphorylation patterns with the expression levels of the signaling molecules that transmit information from the plasma membrane receptor to the nucleus was sought. By using three different cell lines of explanted fibroblasts from gestational day 13 fetal rat skin (n = 24) and 1-month-old postnatal adult rat skin (n = 3), immunoblotting was performed to compare tyrosine phosphorylation patterns. The results revealed five major protein bands of interest in fetal rat fibroblasts, but not in the adult rat fibroblasts. These phosphorylated protein bands are of interest because of their possible role in wound repair and may have the potential to regulate cellular responses to the extracellular matrix and their secondary signaling molecules. It was hypothesized that these bands represented receptor tyrosine kinases, epidermal growth factor receptor, and discoidin domain receptor 1, and their downstream adaptor protein Shc that binds receptor tyrosine kinases to transduce signals intracellularly. Furthermore, elevated expression of platelet-derived growth factor receptor-beta in adult compared with fetal fibroblasts was demonstrated, suggesting that decreased expression of certain growth factors may also be important for the scarless phenomenon to occur.

Adaptor Proteins, Signal Transducing↗
PubMed1979

Initial interaction of human fibroblast and leukocyte interferons with FS-4 fibroblasts.

Human FS-4 cells were exposed to human fibroblast interferon for various times and further incubated in the absence of interferon until challenged with vesicular stomatitis virus. Addition of antibody to fibroblast interferon at the time of removal of interferon did not alter the development of the antiviral state. If cells were exposed to interferon for 45 min at either 0 or 37 degrees C, they developed resistance upon subsequent incubation at 37 degrees C. However, less resistance developed if the cells were initially incubated at 0 degrees C. Our results indicate that a single interaction of fibroblast interferon with susceptible cells, either at 0 or 37 degrees C, is sufficient for the subsequent development of an antiviral state, at least in the short term experiment. The kinetics of development of the antiviral state were compared with fibroblast and leukocyte interferon. The rise in the degree of antiviral resistance was steeper and maximal levels of resistance were reached sooner when FS-4 cells were incubated with increasing concentrations of fibroblast interferon than with leukocyte interferon. This suggests a greater affinity of fibroblast interferon for these cells.

Antibodies↗
PubMed1988

Fibroblasts of two patients with trisomy 18 show 1.5-fold increase in peptidase A activity over normal human diploid fibroblasts.

Peptidase A (Pep A) activity assigned to chromosome 18q23 was biochemically examined in fibroblasts cultured from two patients with trisomy 18 and in fibroblasts derived from normal individuals. The trisomy 18 fibroblasts showed approximately a 1.5-fold increase in Pep A activity over that of the control fibroblasts. Agar gel electrophoretic analysis revealed no detectable differences in the electrophoretic mobility and isoenzyme patterns of Pep A between the trisomy 18 fibroblasts and normal ones. The present results show the trisomy 18 fibroblasts to be suitable for study of the gene dosage effect of Pep A.

Aspartic Acid Endopeptidases↗
PubMed2004

Synovial fibroblasts from rheumatoid arthritis patients differ in their regulation of IL-16 gene activity in comparison to osteoarthritis fibroblasts.

BACKGROUND: In rheumatoid arthritis (RA), synovial fibroblast-like cells (SF) contribute significantly to articular inflammation. They express distinct patterns of genes associated with cell proliferation and differentiation and elevated levels of cytokines and chemoattractant factors, including IL-16. Here we investigated pathways regulating IL-16 expression in fibroblasts from RA patients in comparison to fibroblasts from osteoarthritis (OA) patients. METHODS: Fibroblasts were isolated from dermal and articular biopsies, expanded and pathways of IL-16 induction were investigated by real time quantitative RT/PCR, immuno blot and ELISA. RESULTS: Stimulation of cAMP dependent signal transduction by forskolin induced prominent IL-16 RT/PCR signals in OA-DF and OA-SF. In contrast, in RA-DF and RA-SF staurosporine significantly augmented IL-16 RT/PCR signals, but forskolin induced less IL-16 transcript amounts. Activation of protein kinase C by PMA induced a significant IL-16 response only in RA-SF. Addition of IL-1beta or TNF-alpha did not upregulate IL-16 mRNA but secretion of the mature IL-16 cytokine was activated in serum starved cells in presence of IL-1beta. CONCLUSION: Our results suggest that RA fibroblasts differ from OA fibroblasts with respect to their sensitivities to kinase/phospatase signal transduction pathways. The enhanced expression of IL-16 in the synovial membrane early in RA vs OA may be associated in part with these distinct signaling responses.

Arthritis, Rheumatoid↗
PubMed1986

Cell membrane transport enzymes in cultured dermal fibroblasts from progeroid donors: a comparison to other human fibroblasts.

Cell membranes from progeroid fibroblasts had an elevated Na+, K+ ATPase. Ca++ ATPase and gamma-glutamyl transpeptidase were markedly decreased in progeroid fibroblast membranes. 5'-nucleotide phosphatase was unchanged, compared to age- and sex-matched normal fibroblast membranes. Fetal lung fibroblasts and dermal fibroblast from myotonic dystrophy victims had enzyme activities similar to those of the normal dermal fibroblasts.

Adolescent↗
PubMed1984

Characteristics of cultured lung fibroblasts from bleomycin-treated rats. Comparisons with in vitro exposed normal fibroblasts.

Bleomycin is an antineoplastic agent that causes pulmonary fibrosis. This report describes fibroblasts cultured from lung tissue explants of in vivo bleomycin-exposed and control rats. Proliferation of cultured fibroblasts from bleomycin-exposed lungs was decreased compared with that from control cultures, both in rate of growth and maximal cell yield. The diminished proliferative capacity of these fibroblasts from exposed lungs persisted over 9 wk of serial subcultivation. Fibroblast cultures from exposed lungs typically had a greater proportion of large cells exhibiting extensive cytoskeletal structures than did control cultures. Comparisons of these fibroblasts with normal fibroblasts exposed in vitro to bleomycin showed similarities in size, morphologic features, and proliferation.

Animals↗
PubMed1992

A fibroblast-associated antigen: characterization in fibroblasts and immunoreactivity in smooth muscle differentiated stromal cells.

Fibroblasts with smooth muscle differentiation are frequently derived from human breast tissue. Immunofluorescence cytochemistry of a fibroblast-associated antigen recognized by a monoclonal antibody (MAb), 1B10, was analyzed with a view to discriminating smooth muscle differentiated fibroblasts from vascular smooth muscle cells. The antigen was detected on the cell surface and in cathepsin D-positive and acridine orange-accumulating vesicular compartments of fibroblasts. Ultrastructurally, the antigen was revealed in coated pits and in endosomal and lysosomal structures. 1B10 recognized three major brands migrating at apparent Mr of 38,000, 45,000, and 80,000, in addition to many minor bands between Mr 45,000 and 97,000, including Mr 52,000. The Mr 45,000 and 38,000 were associated with the cell membrane and Mr 52,000 as well as Mr 38,000 were associated with the lysosomes. The 1B10 immunoreactivity was specific to fibroblasts and smooth muscle differentiated fibroblasts within the context of vascular smooth muscle cells.

Actins↗
PubMed2001

Apoptosis in v-myc-transfected MSU-1.1 fibroblasts is induced by cell-matrix contact and differs from that of normal dermal fibroblasts.

In order to characterize a fibroblast cell line representing normal human skin fibroblasts in three-dimensional cultures, we compared the fibroblast line MSU-1.1, derived from human foreskin and immortalized by v-myc, to primary human dermal fibroblasts (NDF). Our results demonstrate that in contrast to NDF, all MSU-1.1 fibroblasts die within 3-4 d when cultured within three-dimensional contractile collagen matrices. Also, in contrast to NDF. MSU-1.1 cells die markedly in anchored collagen gels as well. Death is due to apoptosis and is attenuated by addition of antibodies against collagen-recognizing receptors alpha1beta1 and alpha2beta1. Apoptosis of NDF in collagen lattices was repressed by an inhibitor of caspase-1, which was ineffective on apoptosis of MSU-1.1. Further, apoptosis by MSU-1.l fibroblasts was also observed in anchored, i.e., restrained collagen lattices, an environment that supports proliferation of NDF.

Animals↗
PubMed1988

The uptake and long-term storage of India ink particles and latex beads by fibroblasts in the dermis and subcutis of mice, with special regard to the non-inflammatory defense reaction by fibroblasts.

The fate of India ink particles and polystyrene latex beads injected into the dermis and subcutis of the skin of the auricle and back in mice was observed with the naked eye, light microscopy and electron microscopy. The tattoo patterns made by injected ink particles remained essentially unchanged for life as observed with the naked eye. India ink particles and latex beads were endocytosed by fibroblasts as well as macrophages in the dermis and subcutis. Numerous ink particles or small latex beads (0.22 micron in diameter) were packed into vacuoles 0.1-10.0 micron in diameter which occupied a large volume of the cytoplasm of the cell body and processes of fibroblasts, whereas numerous particles and larger beads (0.22 and 2.0 micron) were taken up into the cell body of macrophages in the vicinity. Most fibroblasts, characterized by long cell processes and well developed rough endoplasmic reticulum, are easily distinguished from macrophages, the latter being round or oval in shape, and having many lysosomes and numerous irregularly shaped microvillous projections. It is believed that fibroblasts taking up and storing the ink particles or latex beads move poorly and are almost fixed in the connective tissue: the tattoos therefore do not change markedly. It is emphasized that the uptake and long-term storage of ink particles and latex beads by the dermal and subcutaneous fibroblasts represent a specific non-inflammatory defense mechanism that protects the living body, without immune reactions, against injuries and invasions by non-toxic foreign agencies. The histiocyte, a term proposed by KIYONO (1914) for a fixed macrophage on the basis of his studies using vital dye staining, is considered to include, in addition to true macrophages, fibroblasts showing endocytotic activities for small foreign bodies such as acid dyes, ink particles, and latex beads.

Animals↗