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PubMedDate not supplied

Autologous adjuvant linked fibroblasts induce anti-glioma immunity: implications for development of a glioma vaccine.

OBJECTIVES: Adjuvant-linked vaccines have been shown to induce anti-tumor immunity in patients with a variety of solid tumors. In this study we describe an in vitro model of active immunotherapy using autologous fibroblasts as immunogen. Correlative results from glioma patients immunized with autologous fibroblasts are also described. METHODS: Peripheral blood lymphocytes (PBLs) from normal subjects were immunized in vitro against autologous skin fibroblasts coupled to the adjuvant muramyl dipeptide. The lymphocytes developed cell-mediated cytotoxicity that was measured with a short-term chromium release assay. Results of in vitro experiments were compared to data derived from glioma patients immunized with subcutaneous injection of an autologous adjuvant-linked fibroblast vaccine. Glioma target cells and fibroblast immunogens were derived from early passage primary tissue culture. RESULTS: A comparison of autologous vs. homologous immunogen indicated that major histocompatibility complex matching was required at the sensitization stage of immunity (17.2 +/- 3.4% specific lysis vs. 0.4 +/- 3.1%, P < 0.01). Pre-treatment of fibroblast immunogen cells with interferon gamma (IFN-gamma) was found to significantly increase immunity (42.2 +/- 10.0%, P < 0.01), as did IFN-gamma pre-treatment of tumor target cells (35.8 +/- 9.0%, P < 0.01). The positive effect of IFN-gamma was diminished by treatment of cells with IFN-alpha. These in vitro results correlated well with in vivo data derived from glioma patients immunized with an autologous adjuvant-linked fibroblast vaccine. PBLs from patients developed direct cell-mediated cytotoxicity against autologous tumor cells. Lysis of tumor targets after in vivo immunization increased over a three-week interval (from 1.2 +/- 3.0% to 21.0 +/- 3.4%, P < 0.01) while lysis of a non-MHC matched control cell line remained essentially unchanged. CONCLUSIONS: Specific lysis of glioma targets in vitro was achieved after in vivo sensitization with autologous adjuvant-linked fibroblasts. Collectively, the data indicate that biochemically modified autologous cells can stimulate anti-glioma immunity in humans. The degree of specific immunity seen in our patients compares favorably with other published series using glioma cells as an antigenic source. Accordingly, fibroblasts may represent a practical alternative to glioma cells for vaccine construction.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMedDate not supplied

Treatment with allogeneic interleukin-2 secreting fibroblasts protects against the development of malignant brain tumors.

We have reported that mice with an intracerebral (i.c.) malignant glioma or breast cancer treated with i.c. injection of allogeneic fibroblasts genetically engineered to secrete interleukin-2 (IL-2) survived longer than mice in various control groups. The goal of the present study was to determine the effectiveness of utilizing IL-2 secreting allogeneic fibroblasts as a protective treatment to prevent the development of an i.c. glioma or breast carcinoma. Using an intracranial microcannula system that we developed, the animals received weekly injections of the cellular vaccine prior to the introduction of tumor cells via the cannula. The results demonstrate a significant delay (P < 0.005) in the development of glioma in the animals pre-treated with either allogeneic non-secreting or IL-2-secreting fibroblasts prior to introduction of tumor cells. In addition, 50% of the animals pre-treated with IL-2 secreting allogeneic fibroblasts injected subsequently with G1261 glioma cells did not develop a tumor, while all of the animals injected with glioma cells alone and 92% of those treated with non-secreting fibroblasts eventually died. The long-term survivors from the pre-treatment group were subsequently re-challenged with tumor and compared to naive controls. There was evidence that long-term immunity was established in the pre-treated animals, since there was a significant prolongation of survival (P < 0.01). In similar experiments using breast cancer cells, 62% of the animals pre-treated with non-secreting allogeneic fibroblasts and 75% of the animals pre-treated with allogeneic IL-2 secreting fibroblasts subsequently injected with SB-5b breast carcinoma cells did not develop tumors and had a significant prolongation of survival. These data suggest that i.c. injection of allogeneic IL-2 secreting fibroblasts are effective as a protective treatment in the prevention of the development of a brain tumor when the fibroblasts are introduced into the same site where the tumor is subsequently injected.

Adenocarcinoma↗

PubMed1984

Promotion of collagen production by human fibroblasts with gastric cancer cells in vitro.

To elucidate the histogenesis of gastric scirrhous cancer, the promotion of collagen production by normal human skin fibroblasts (HSF-1) with human gastric cancer cells (KATO-III, MKN-45 and MKN-28) was investigated by direct coculture and parabiotic culture. Argyrophilic collagenous fibers were demonstrated among fibroblasts on both direct cocultures and parabiotic cultures of the fibroblasts with gastric cancer cells. Microscopic examination showed that these fibers appeared earlier and were more abundant and thicker in direct cocultures and parabiotic cultures than in single cultures of fibroblasts. Gastric cancer cells in single or parabiotic culture did not form argyrophilic fibers. For quantitative proof of the promotion of collagen production by fibroblasts with gastric cancer cells, hydroxyproline produced by fibroblasts was measured. Much higher fibroblast hydroxyproline values were obtained in parabiotic cultures with gastric cancer cell lines than in single cultures of HSF-1. Moreover, the rate of collagen synthesis by HSF-1 was much higher than that of any gastric cancer cell line tested. These results demonstrate that gastric cancer cells enhance collagen production by fibroblasts in vitro. This finding suggests that they may produce a factor promoting fibroblast collagen synthesis and that this may contribute to the formation of stromal collagen in human gastric scirrhous cancer.

Adenocarcinoma, Scirrhous↗

PubMed2001

The IL-6 family cytokines, interleukin-6, interleukin-11, oncostatin M, and leukemia inhibitory factor, enhance mast cell growth through fibroblast-dependent pathway in mice.

Mast cell hyperplasia is observed in various inflammatory skin diseases. Although the mechanisms involved in the pathogenesis of these conditions remains largely uninvestigated, it is speculated that mediators produced in the lesional skin provide a favorable microenvironment for mast cell growth. Among the proinflammatory mediators, leukemia inhibitory factor (LIF), which shares a receptor component (gp130 subunit) with interleukin-6 (IL-6), has been identified as a mast cell growth-enhancing factor produced by cells of the keratinocyte-derived cell line (KCMH-1). In this study, we investigated the effect of four IL-6 family cytokines, IL-6, IL-11, oncostatin M (OSM) and LIF on mast cell growth in a mast cell/fibroblast co-culture system. When mouse bone marrow-derived cultured mast cells (BMMC) were maintained on a NIH/3T3 fibroblast monolayer, these cytokines induced proliferation of the mast cells, but none of the cytokines had any effect on mast cell proliferation in the absence of fibroblasts. mRNA for gp130 and receptors for the four IL-6 family cytokines were detected in NIH/3T3 fibroblasts by reverse transcriptase-mediated polymerase chain reaction. In contrast, only mRNA for the IL-11 receptor and gp130 were detected in BMMC. Tyrosine phosphorylation of gp130 was observed in NIH/3T3 fibroblasts after stimulation with all the cytokines. Some IL-6 family cytokines enhanced the production of stem cell factor (SCF), a potent mast cell growth factor, from NIH/3T3 fibroblasts, but the amount of SCF produced by NIH/3T3 fibroblasts was not paralleled by the mast cell growth-enhancement induced by the IL-6 family cytokines. When anti-SCF antibody was added with the IL-6 family cytokines in the BMMC/fibroblast coculture system, a significant effect of these cytokines remained, although the growth-enhancing activity was markedly reduced. A similar result was obtained when BMMC were prepared from W/W(V)-mice, which lack functional c-kit, in the BMMC/ fibroblast coculture system. These results suggest that IL-6 family cytokines stimulate mast cell growth by a fibroblast-dependent mechanism, and also suggest the existence of another pathway between BMMC and NIH/3T3 fibroblasts cooperating with the SCF/c-kit pathway. IL-6 family cytokines may thus contribute to mast cell hyperplasia in skin diseases.

3T3 Cells↗

PubMed2002

Protease nexin-1 messenger RNA levels are not affected by serum or interferon beta in cultured systemic sclerosis fibroblasts.

The aim of the present study was to analyze the effect of serum and human recombinant beta interferon (rIFNbeta) treatment on PN-1 mRNA levels in cultured dermal fibroblasts obtained from the skin of healthy donors and from lesional skin of systemic sclerosis (SSc) patients with the limited (CREST syndrome) or the diffuse form of SSc. Total RNA was isolated from fibroblasts derived from the skin of healthy individuals and from lesional skin of patients with CREST syndrome and the diffuse form of SSc cultured under different conditions (1% or 10% serum-supplemented medium) and treated with 500 IU/ml of rIFNbeta. PN-1 gene expression was assessed by Northern blot analysis. We detected variable PN-1 mRNA levels in normal control fibroblasts as well as in SSc fibroblasts under the different culture conditions (1% or 10% serum-supplemented medium). Accumulated PN-1 mRNA levels found in normal cultured fibroblasts were similar to or even higher than in SSc fibroblasts. PN-1 messenger levels were not significantly altered by IFNbeta treatment in normal or SSc cultured fibroblasts despite the presence of an IFN-stimulated responsive element (ISRE) in the promoter of the PN-1 gene. Our findings suggest that PN-1 expression in SSc fibroblasts at the mRNA level requires further investigation in a large number of SSc patients to better characterize the role of this serpin in the pathogenesis of SSc. We conclude that the transcriptional regulation of PN-1 is not associated with IFNbeta, an antifibrotic cytokine naturally produced by fibroblasts.

Adolescent↗

PubMed1998

Growth factors in cultured pterygium fibroblasts: immunohistochemical and ELISA analysis.

BACKGROUND: In order to study growth factors in the pathogenesis and recurrence of pterygium, we grew pterygium tissues in culture and compared fibroblasts from primary and from recurrent pterygia with reference to the fibroangiogenic growth factors basic fibroblast growth factor (b-FGF), platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNF-alpha). METHODS: We used indirect immunohistochemical procedures against human b-FGF, PDGF, TGF-beta and TNF-alpha. As controls, we used cultured normal human conjunctival fibroblasts. A serum-free conditioned medium (CM) from confluent fibroblasts derived from primary and recurrent explants was assessed by enzyme-linked immunosorbent assay to determine the level of the above-mentioned growth factors. RESULTS: Immunoreactivity of b-FGF was stronger in recurrent than in primary pterygium fibroblasts. PDGF immunolabeling was stronger in primary than in recurrent pterygium fibroblasts. TGF-beta and TNF-alpha immunolabeling was weak in both pterygia. All these growth factors were very sparse in normal conjunctival fibroblasts. Basic-FGF and TGF-beta 1 were found in the CM from both primary and recurrent pterygium, while PDGF and TNF-alpha were not detectable. CONCLUSION: The strong immunoreactivity and the release of b-FGF in cultured fibroblasts of recurrent pterygia suggest that fibroblasts may play an important role in the recurrence of pterygium.

Adult↗

PubMed2005

Interaction of keratinocytes and fibroblasts modulates the expression of matrix metalloproteinases-2 and -9 and their inhibitors.

Disruption of epidermal-mesenchymal communication due to a delay in epithelialization, increases the frequency of developing fibrotic conditions in skin. As matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) are two key enzymes involved in wound healing and tissue remodeling, here we examined the efficacy of keratinocyte-fibroblast interaction on modulation of these enzymes and their inhibitors. The conditioned media derived from keratinocytes and fibroblasts grown in upper and lower chambers of a co-culture system, respectively, were analyzed for MMP-2 and -9. Keratinocyte or fibroblast conditioned medium (FCM) was used as a control. Gelatinolytic activity analyzed by zymography showed that keratinocytes mainly express MMP-9 and to a lesser extent MMP-2; while fibroblasts express only MMP-2. In a co-culture system, the activities of both MMP-2 and MMP-9 markedly increased in conditioned media collected from bottom chambers. These findings were consistent with the level of MMP-2 and MMP-9 measured by Western blot. Using the same experimental setting, the levels of tissue inhibitors of MMPs (TIMPs) secreted by keratinocytes and fibroblasts grown in the same co-culture system were also evaluated. Western blot showed that fibroblasts secrete only TIMP-1 and TIMP-2 whose levels were increased by co-culturing fibroblasts with keratinocytes. In contrary the level of TIMP-3, which was mainly expressed by keratinocytes, increased by co-culturing these cells with fibroblasts. In conclusion, interaction of fibroblast-keratinocyte modulates the levels of MMP-2 and -9 and their inhibitors produced by these cells and this interaction may be critical for a better healing quality at a late stage of the wound healing process.

Cell Communication↗

PubMed1997

Characterization of a SV40-transformed rheumatoid synovial fibroblast cell line which retains genotypic expression patterns: a model for evaluation of anti-arthritic agents.

A chimeric Adenovirus-Simian Virus 40 (AdSV40) containing the large T antigen was used to transform rheumatoid synovial fibroblasts. A rheumatoid synovial fibroblast cell line was established by infection of primary rheumatoid arthritis (RA) synovial fibroblasts at Passage 10 with AdSV40 recombinants followed by selection in semisoft agarose cultures. The transformed cells grew anchor independent, exhibited continuous proliferation (> 65 passages) in monolayer culture, and formed multiple visible foci. The transformed synovial fibroblasts showed expression of the simian virus 40 large T antigen in the nucleus as determined by immunofluorescence staining. In addition, indirect immunofluorescence staining demonstrated that the transformed cells stained specifically with a fibroblast-specific antibody 1B10. Studies involving expression of metalloproteinases showed that collagenase and stromelysin were induced by phorbal 12-myristate 13-acetate (PMA), and such an induction was repressed by dexamethasone typical of primary RA fibroblasts. Levels of mRNAs for IL-1 beta, TNF-alpha, and c-jun were increased by PMA, and the mRNA transcripts of these genes were also repressed by addition of dexamethasone to the culture media. Our results indicate that transformed RA synovial fibroblasts display a similar gene expression pattern in response to PMA and dexamethasone as observed for untransformed primary RA synovial fibroblasts. These transformed rheumatoid arthritis synovial fibroblast cells provide an ideal cell culture model in which to test the efficacy of novel arthritis gene therapy reagents.

Antirheumatic Agents↗

PubMed1998

Fibronectin production by cultured human lung fibroblasts in three-dimensional collagen gel culture.

In vivo, fibroblasts are distributed in a three-dimensional (3-D) connective tissue matrix. Fibronectin is a major product of fibroblasts in routine cell culture and is thought to regulate many aspects of fibroblast biology. In this context, we sought to determine if the interaction of fibroblasts with a 3-D matrix might affect fibronectin production. To examine this hypothesis, fibronectin production by fibroblasts cultured in a 3-D collagen gel or on plastic dishes was measured by ELISA. Fibroblasts in 3-D gel culture produced more fibronectin than those in monolayer culture. Fibroblasts in 3-D culture produced increasing amounts of fibronectin when the collagen concentration of the gel was increased. The 3-D nature of the matrix appeared to be crucial because plating the fibroblasts on the surface of a plastic dish underneath a collagen gel was not different from plating them on a plastic dish in the absence of collagen. In addition to increased fibronectin production, the distribution of the fibronectin produced in 3-D culture was different from that of monolayer culture. In monolayer culture, more than half of the fibronectin was released into the culture medium. In 3-D culture, however, approximately two-thirds remained in the collagen gel. In summary, the presence of a 3-D collagen matrix increases fibroblast fibronectin production and results in greater retention of fibronectin in the vicinity of the producing cells.

Blotting, Northern↗

PubMed1994

Differences in adhesion and collagen gel contraction between fibroblasts from various types of odontogenic cyst.

Fibroblasts were grown from explants of normal gingiva and foreskin, and from walls of dentigerous, radicular and residual cysts, as well as keratocysts of basal-cell naevus syndrome and non-syndrome origin. Dentigerous-cyst fibroblast adhesion to poly-L-lysine-coated glass was unaffected by all adhesion-related glycoproteins. Chondroitin sulphate, fibronectin and heparan sulphate enhanced attachment of all other fibroblasts. Chondroitin-sulphate and fibronectin-enhanced adhesion was blocked by an arg-gly-asp peptide. Fibronectin, chondroitin sulphate and laminin all promoted collagen lattice contraction using normal gingival fibroblasts and low-serum media. Fibronectin had a greater effect than chondroitin sulphate and laminin. In media with standard serum, all cyst fibroblast lines examined demonstrated similar gel contraction curves with the exception of dentigerous cyst-derived fibroblasts, which contracted at decreased rates. Suppression of gel contraction was seen with dentigerous-cyst fibroblasts with all extracellular matrix glycoproteins and low serum. Dentigerous-cyst fibroblast attachment to glass and behaviour in gel lattices suggest that these cells express different functional attachment factors from other cyst fibroblast types.

Adolescent↗

PubMed1981

Correlation between the regeneration of cell surface glycoproteins and the cell re-adhesion to the substratum in trypsin-treated chick fibroblasts at various stages of embryo development.

The ability of fibroblasts from 8- to 16-day-old chick embryos to adhere to a substratum was altered by trypsin treatment. The consequences of this treatment were investigated on cell re-adhesion to the substratum and cell morphology in relation to the regeneration of cell surface glycoproteins as estimated by the incorporation of [3H]leucine and [14C]glucosamine. Cell re-adhesion, cell shape and restoration of cell surface glycoproteins of the fibroblasts from chick embryos were markedly alike for each stage of embryo development. Age-dependent differences were noted. The fibroblasts from 8-day-old embryos re-adhered progressively more rapidly than fibroblasts from 16-day-old embryos. The fibroblast morphology appeared to be dependent on the re-adhesion of cells to the substratum. Parallel to the re-adhesion, the cell surface glycoprotein recovery reached at least 90% in fibroblasts from 8-day-old embryos and only about 70% in fibroblasts from 16-day-old embryos after a 4 h culture as compared to the control cultures. These percentages coincided with 73% (fibroblasts from 8-day-old embryos) and 40% (fibroblasts from 16-day-old embryos) adhesion recovery. The results are discussed in terms of a possible mechanism for cell surface recovery.

Animals↗

PubMed1983

The intralysosomal pH in cultured human skin fibroblasts in relation to cystine accumulation in patients with cystinosis.

The intralysosomal pH in cultured skin fibroblasts from a patient with cystinosis and from control fibroblasts was estimated by the method of Hollemans et al. (Hollemans, M., Oude Elferink, R.P.J., de Groot, P.G., Strijland, A. and Tager, J.M. (1981) Biochim. Biophys. Acta 643, 140-151). 1. The intralysosomal pH in cystinotic fibroblasts (5.37 +/- 0.04; n = 12) was almost identical to that in the control fibroblasts (5.27 +/- 0.06; n = 10). 2. After depletion of cystine by pretreatment of cystinotic fibroblasts with 1 mM cysteamine, there was no significant change in the intralysosomal pH. Incubation of either cystinotic or control fibroblasts with higher concentrations of cysteamine (10 or 25 mM) led to an increase in intralysosomal pH similar to that seen with other weak bases. 3. The fractional volume of the lysosomes in cystinotic fibroblasts (0.100 +/- 0.012; n = 4) was higher than that in control fibroblasts (0.039 +/- 0.010; n = 4). 4. It is concluded, in contrast to Jonas et al. (Jonas, A.J., Smith, M.L. and Schneider, J.A. (1982) J. Biol. Chem. 257, 13185-13188), that the lysosomal proton-translocating ATPase (Okhuma, S., Moriyama, Y. and Takano, T. (1982) Proc. Natl. Acad. Sci. USA 79, 2758-2762) is not impaired in cystinotic fibroblasts.

Cysteamine↗

PubMed1983

Identification of thiol:protein disulfide oxidoreductase activity in cultured human fibroblasts: dependence of enzyme activity on growth conditions.

Thiol:protein disulfide oxidoreductase activity was assayed in extracts of cultured normal human skin fibroblasts. Enzyme activity in confluent fibroblasts was dependent on growth conditions. In serum-deprived fibroblasts grown in minimal medium enzyme activity was approximately 40% of that observed in fibroblasts maintained in medium supplemented with 10% fetal calf serum. In fibroblasts cultured in medium supplemented only with insulin, activity was 35% greater than that in fibroblasts cultured in unsupplemented defined medium. Antibodies raised against purified bovine liver thiol:protein disulfide oxidoreductase immunoprecipitated all of the activity present in fibroblast extracts. The thiol:protein disulfide oxidoreductase from human fibroblasts thus appears to share antigenic determinants with the bovine liver enzyme. The human fibroblast may serve as an in vitro model to study the regulation of the oxidoreductase.

Blood↗

PubMed1989

Extracellular matrix organization modulates fibroblast growth and growth factor responsiveness.

To learn more about the relationship between extracellular matrix organization, cell shape, and cell growth control, we studied DNA synthesis by fibroblasts in collagen gels that were either attached to culture dishes or floating in culture medium during gel contraction. After 4 days of contraction, the collagen density (initially 1.5 mg/ml) reached 22 mg/ml in attached gels and 55 mg/ml in floating gels. After contraction, attached collagen gels were well organized; collagen fibrils were aligned in the plane of cell spreading; and fibroblasts had an elongated, bipolar morphology. Floating collagen gels, however, were unorganized; collagen fibrils were arranged randomly; and fibroblasts had a stellate morphology. DNA synthesis by fibroblasts in contracted collagen gels was suppressed if the gels were floating in medium but not if the gels were attached, and inhibition was independent of the extent of gel contraction. Therefore, growth of fibroblasts in contracted collagen gels could be regulated by differences in extracellular matrix organization and cell shape independently of extracellular matrix density. We also compared the responses of fibroblasts in contracted collagen gels and monolayer culture to peptide growth factors including fibroblast growth factor, platelet-derived growth factor, transforming growth factor-beta, and interleukin 1. Cells in floating collagen gels were generally unresponsive to any of the growth factors. Cells in attached collagen gels and monolayer culture were affected similarly by fibroblast growth factor but not by the others. Our results indicate that extracellular matrix organization influenced not only cell growth, but also fibroblast responsiveness to peptide growth factors.

Cell Adhesion↗

PubMed1992

Alpha-smooth muscle actin is expressed in a subpopulation of cultured and cloned fibroblasts and is modulated by gamma-interferon.

Clinical and experimental investigations have shown that, during wound healing and fibrocontractive diseases, fibroblasts acquire, more or less permanently according to the situation, morphological and biochemical features of smooth muscle (SM) cells including the expression of alpha-SM actin. Primary and passaged cultures of rat and human fibroblasts contain a subpopulation of cells expressing alpha-SM actin. These cells could derive from SM cells and/or pericytes present in the tissue from which cultures have been produced or represent bona fide fibroblasts. We have investigated the presence of alpha-SM actin in fibroblast cultures, clones, and subclones. In all cases the fibroblastic populations studied showed a proportion of alpha-SM actin expressing cells. Even after cloning, we never obtained populations negative for alpha-SM actin. We conclude that alpha-SM actin expression in fibroblastic cultures is not due to contaminant cells but is a feature of fibroblasts themselves. Our results support the view that fibroblastic cells are a heterogeneous population. It has been previously shown that gamma-interferon (gamma-IFN) decreases alpha-SM actin expression in SM cells. In rat and human fibroblasts, gamma-IFN decreases alpha-SM actin protein and mRNA expression as well as proliferation. The properties of this cytokine make it a good candidate for exerting an anti-fibrotic activity in vivo.

Actins↗

PubMed1992

Increased collagen type III synthesis by fibroblasts isolated from strictures of patients with Crohn's disease.

Increased type III collagen deposition in all layers of the intestinal tract, including the lamina propria, is a common feature of strictures in Crohn's disease. In the present study, it was found that in comparison with fibroblasts from normal or nonstrictured but inflamed intestinal lamina propria, the fibroblasts isolated from strictures of patients with Crohn's disease produce significantly more collagen, especially collagen type III. Transforming growth factor beta 1 (TGF-beta 1) significantly increased collagen type III synthesis in intestinal lamina propria fibroblasts isolated from all patients. The effect of TGF-beta 1 on type III collagen synthesis in fibroblasts from strictures in Crohn's disease was significantly higher than that in fibroblasts from inflamed specimens of the same patients. In contrast, platelet-derived growth factor decreased collagen type III synthesis in lamina propria fibroblasts derived from strictures compared with fibroblasts from nonstrictured but inflamed tissue. These findings indicate that fibroblasts in the lamina propria of patients with Crohn's disease have a different reactivity towards cytokines. On the basis of increased type III collagen deposition in intestinal strictures of Crohn's disease by using cell adhesion and cell proliferation assays, it was shown that collagen type III stimulated adhesion and proliferation of lamina propria fibroblasts. The current data provide evidence that the different reactivity of mesenchymal cells to cytokines in terms of synthesizing type III collagen fibrils, which is a major component of collagen fibrils, may play an important role in the pathogenesis of fibrosis and stricture formation in chronic inflammatory bowel diseases.

Adult↗

PubMed1992

Spatial and functional relationship between myocytes and fibroblasts in the rabbit sinoatrial node.

In an attempt to understand better the directional differences in conduction velocity in the rabbit sinoatrial node, a possible conductive role of the abundant connective tissue surrounding the myocytes has been investigated. In particular, starting from the finding of communicating junctions between heart muscle cells and fibroblasts in tissue culture, heterologous gap junctions were searched for in thin sections of the rabbit sinoatrial node. Within and at the edge of nodal cell clusters, fibroblasts often show thin sheet-like extensions parallel to the surface of myocytes. In contrast to the intimately contacting myocytes, fibroblast extensions are kept separated from the myocytes by the basement membrane of the latter. Besides some rare undefined membrane appositions a single tiny gap junction-like structure was found between a fibroblast and a myocyte in a tissue area in which the calculated number of gap junctions between myocytes amounts from 1.10(4) to 3.10(4). Yet, fibroblasts are linked together regularly by small gap junctions containing a wider gap than the junctions between the myocytes (1.4 +/- 0.4 nm vs. 1.0 +/- 0.4 nm, resp., P less than 0.05). As an alternative to direct electrical coupling, the possibility of interaction between fibroblasts and nodal cells by capacitive coupling has been considered. Model calculations based on the reconstruction of some fibroblast extensions parallel to nodal cells show that the current which can be transmitted from discharging nodal cells to fibroblasts is negligible. It is concluded that fibroblasts do not participate in the impulse conduction within the sinoatrial node. The origin of the directional differences in conduction velocity in the sinoatrial node must be found in the spatial arrangement of the myocytes and the distribution of the gap junctions between these cells only.

Animals↗

PubMed1996

Interleukin-2 inhibits 3T3 fibroblast proliferation.

In order to clarify the role played by interleukin-2 (IL-2) in the regulation of fibroblast function, we investigated the effect of rat IL-2 and human recombinant IL-2 on 3T3 fibroblast proliferation and collagen synthesis. Fibroblasts were incubated with various concentrations of IL-2 for different periods of time. IL-2 was found to decrease in time- and dose-dependent manner the proliferation of 3T3 fibroblasts. This effect correlated with ability of IL-2 to enhance PGE2 production by 3T3 fibroblasts. When 3T3 fibroblasts were cocultured with rat peritoneal mast cells (MC), the growth-inhibiting effect of IL-2 was significantly less pronounced. Treatment of the cultures with IL-2 had no effect on collagen production by both 3T3 fibroblasts and fibroblasts cocultured with MC. In conclusion, in this study we provide evidence that IL-2, the key cytokine in T-cell growth and differentiation, can affect fibroblast functions.

3T3 Cells↗