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Biomedical subjects

A E Postlethwaite

Publications and source records attributed to A E Postlethwaite.

At least 55 records · Page 3Linked to original sources
PubMed1989

Stimulation of glycosaminoglycan synthesis in cultured human dermal fibroblasts by interleukin 1. Induction of hyaluronic acid synthesis by natural and recombinant interleukin 1s and synthetic interleukin 1 beta peptide 163-171.

Hyaluronic acid (HA) is believed to play a critical role in wound healing and in morphogenesis. Factors controlling the production of HA by fibroblasts in normal and pathological states are not completely understood. In this report we have observed that natural human interleukin (IL-1)1 beta and human recombinant (hrIL)-1 alpha and beta are potent stimulators of HA production by fibroblasts in vitro. Hyaluronic acid is the major species of glycosaminoglycan (GAG) stimulated by IL-1 in fibroblasts. PGE2 does not appear to be involved directly in this IL-1 effect on fibroblasts, but stimulation of HA production by IL-1 is dependent on protein synthesis. The synthetic human IL-1 beta peptide 163-171 (Val-Gln-Gly-Glu-Glu-Ser-Asn-Asp-Lys), which has been previously shown to stimulate thymocyte proliferation but not fibroblast PGE2 production, is also able to stimulate fibroblast HA production. The synthesis and secretion of IL-1 by mononuclear phagocytes at sites of inflammation and immune reactions in vivo could potentially serve as a signal for fibroblasts to synthesize HA, which in turn could serve to facilitate and modulate reparative and immune processes by virtue of its ability to alter cell-cell, cell matrix, and cell-membrane receptor interactions.

Cells, Cultured↗
PubMed1989

Pamidronate sodium and calcitonin-resistant Paget's disease. Immediate response in a patient.

One three-day course of intravenous pamidronate sodium (3-amino-1-hydroxypropylidene-1,1-bisphosphonate), 30 mg/d, in a patient with calcitonin-resistant Paget's disease resulted in the following: marked clinical improvement within two weeks; normalization of urinary hydroxyproline value; fall of serum alkaline phosphatase value (900 to 250 U/L); a rise in serum osteocalcin value by the tenth week that returned to pretreatment levels in the 16th week; transient hypocalcemia with elevation of parathyroid hormone value; reduction in urinary calcium excretion; and improvement in bone scans. No adverse reactions occurred, with the exception of mild and transient hyperpyrexia for 48 hours during pamidronate administration. White blood cell counts did not change and serum interleukin 1 was undetectable before and after treatment with pamidronate. Pamidronate seems to be highly effective in the treatment of Paget's disease of the bone, but its profound effects on mineral and bone metabolism require close monitoring during the short-term period of intravenous treatment.

Alkaline Phosphatase↗
PubMed1988

Regulation of mRNAs for type-1 plasminogen activator inhibitor, fibronectin, and type I procollagen by transforming growth factor-beta. Divergent responses in lung fibroblasts and carcinoma cells.

Transforming growth factor-beta (TGF beta) is a growth modulator which stimulates the growth of fibroblasts but acts as a strong growth inhibitor for cells of epithelial origin. TGF beta also influences the production of extracellular matrix proteins and of proteases and protease inhibitors by cultured cells. One important protease inhibitor whose production is affected rapidly by TGF beta is the type-1 plasminogen activator inhibitor (PAI-1). To investigate the relationships between PAI-1 and the extracellular matrix, we analyzed the regulation by TGF beta of PAI-1, fibronectin, and type I procollagen in malignant human lung carcinoma cells (A549) and in human lung fibroblasts (WI-38). The expression of the respective genes was examined by polypeptide analyses and by measurements of the steady-state levels of the corresponding mRNAs by Northern hybridization. The mRNA levels for PAI-1 were elevated rapidly by TGF beta in both cell lines. This induction occurred in the presence of cycloheximide and thus was not dependent on protein synthesis. In fact, the effects of TGF beta and cycloheximide on PAI-1 mRNA were additive. In contrast, the induction of fibronectin, beta-actin, and type I procollagen (synthesized only in WI-38 cells) was abrogated by cycloheximide. In general, the effects of TGF beta on the steady-state levels of mRNAs for fibronectin, actin, and type I procollagen mRNA were similar in the two cell types. However, the production of PAI-1 mRNA in response to TGF beta differed in the two cell types, being transient (peak within 5 h) in the carcinoma cells and more persistent in fibroblasts. Thus, the major difference in TGF beta regulation of PAI-1 mRNA between lung fibroblasts and carcinoma cells was the duration of the effect. These results, together with previous data, suggest that PAI-1 and plasminogen activators may be regulated oppositely by TGF beta. We therefore propose a model for TGF beta in the regulation of extracellular proteolytic activity.

Actins↗
PubMed1988

Modulation of fibroblast functions by interleukin 1: increased steady-state accumulation of type I procollagen messenger RNAs and stimulation of other functions but not chemotaxis by human recombinant interleukin 1 alpha and beta.

Interleukin-1 (IL-1) is synthesized by and released from macrophages in response to a variety of stimuli and appears to play an essential role in virtually all inflammatory conditions. In tissues of mesenchymal origin (e.g., cartilage, muscle, bone, and soft connective tissue) IL-1 induces changes characteristic of both destructive as well as reparative phenomena. Previous studies with natural IL-1 of varying degrees of purity have suggested that it is capable of modulating a number of biological activities of fibroblasts. We have compared the effects of purified human recombinant (hr) IL-1 alpha and beta on several fibroblast functions. The parameters studied include cell proliferation, chemotaxis, and production of collagen, collagenase, tissue inhibitor of metalloproteinase (TIMP), and prostaglandin (PG) E2. We observed that hrIL-1s stimulate the synthesis and accumulation of type I procollagen chains. Intracellular degradation of collagen is not altered by the hrIL-1s. Both IL-1s were observed to increase the steady-state levels of pro alpha 1(I) and pro alpha 2(I) mRNAs, indicating that they exert control of type I procollagen gene expression at the pretranslational level. We found that both hrIL-1 alpha and beta stimulate synthesis of TIMP, collagenase, PGE2, and growth of fibroblasts in vitro but are not chemotactic for fibroblasts. Although hrIl-1 alpha and beta both are able to stimulate production of PGE2 by fibroblasts, inhibition of prostaglandin synthesis by indomethacin has no measurable effect on the ability of the IL-1s to stimulate cell growth or production of collagen and collagenase. Each of the IL-1s stimulated proliferation and collagen production by fibroblasts to a similar degree, however hrIL-1 beta was found to be less potent than hrIL-1 alpha in stimulating PGE2 production. These observations support the notion that IL-1 alpha and beta may both modulate the degradation of collagen at sites of tissue injury by virtue of their ability to stimulate collagenase and PGE2 production by fibroblasts. Furthermore, IL-1 alpha and beta might also direct reparative functions of fibroblasts by stimulating their proliferation and synthesis of collagen and TIMP.

Cell Division↗
PubMed1987

Fibroblast stimulation in schistosomiasis. VII. Egg granulomas secrete factors that stimulate collagen and fibronectin synthesis.

Tissue fibrosis in schistosomiasis is largely responsible for the important morbidity that results from infection with the trematode worms, Schistosoma. Neither the migrating larval forms (cercariae) nor the intravascular adult worms appear to incite pathological responses that are important in chronic schistosomiasis. On the other hand, eggs deposited in tissue incite chronic granulomatous inflammatory responses that are the hallmark of infection and precede the onset of adjacent tissue fibrosis. We previously reported that products of the egg granulomas can stimulate a number of relevant responses in fibroblast cultures that in vivo would be expected to promote tissue fibrosis. We report here that the granulomas secrete factors that in vitro can stimulate collagen and fibronectin synthesis in fibroblasts. We determined that activity stimulating collagen synthesis is congruent to 10 Kd (gel filtration) with a pI of congruent to 5.5 (isoelectric focusing); additional activity is also detected in some other fractions (congruent to Kd; pI approximately 7.0). In contrast, the activity stimulating fibronectin synthesis was congruent to 22 Kd with a pI of 5.5. Activity was also present in fractions of 50 Kd with pI of approximately 7.5. Fibroblasts grown in granuloma supernatant-containing medium contained greater steady-state levels of specific mRNA coding for type I procollagen and fibronectin compared with cells cultured in unsupplemented medium. These observations support the hypothesis that biologically active molecules secreted by granuloma cells are instrumental in the initiation of tissue fibrosis in schistosomiasis.

Animals↗
PubMed1987

Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta.

Transforming growth factor beta (TGF-beta) is a potent chemoattractant in vitro for human dermal fibroblasts. Intact disulfide and perhaps the dimeric structure of TGF-beta is essential for its ability to stimulate chemotactic migration of fibroblasts, since reduction with 2-ME results in a marked loss of its potency as a chemoattractant. Although epidermal growth factor (EGF) appears to be capable of modulating some effects of TGF-beta, it does not alter the chemotactic response of fibroblasts to TGF-beta. Specific polyvalent rabbit antibodies to homogeneously pure TGF-beta block its chemotactic activity but has no effect on the other chemoattractants tested (platelet-derived growth factor, fibronectin, and denatured type I collagen). Since TGF-beta is secreted by a variety of neoplastic and normal cells including platelets, monocytes/macrophages, and lymphocytes, it may play a critical role in vivo in embryogenesis, host response to tumors, and the repair response that follows damage to tissues by immune and nonimmune reactions.

Blood Platelets↗
PubMed1987

Identification of a protein in sera of normal humans that inhibits fibroblast chemotactic and random migration in vitro.

Normal human serum contains a 230,000 Mr protein that inhibits fibroblast chemotactic and random migration. This serum inhibitor of fibroblast migration (SIFM) is a heat-stable, trypsin-sensitive protein with a pI of 4.8 that reversibly inhibits the random and chemotactic migration of fibroblasts in vitro. Although SIFM effectively inhibits the chemotaxis of fibroblasts to interstitial collagens, fibronectin, lymphocyte-derived chemotactic factor for fibroblasts, and serum-derived chemotactic factor, it does not alter the chemotactic migration of human peripheral blood neutrophils or monocytes, and does not act as a cytotoxin to human dermal fibroblasts. The SIFM appears to act through a cell-directed mechanism to alter the fibroblast's ability to migrate. Serum inhibitor of fibroblast migration may function in vivo to modulate fibroblast migration under physiologic and pathologic conditions.

Blood Proteins↗
PubMed1987

Transforming growth factor-beta increases steady state levels of type I procollagen and fibronectin messenger RNAs posttranscriptionally in cultured human dermal fibroblasts.

Transforming growth factor-beta (TGF beta), when injected subcutaneously into newborn mice, induces a rapid fibrotic response, stimulates chemotaxis, and elevates the rates of biosynthesis of collagen and fibronectin by fibroblasts in vitro. We explored the molecular mechanisms of TGF beta-mediated stimulation of collagen and fibronectin synthesis in cultured human foreskin fibroblasts. TGF beta preferentially stimulated the synthesis of fibronectin and type I procollagen chains 3-5-fold as shown by polypeptide analysis. Concomitant elevation in the steady state levels of messenger RNAs (mRNAs) coding for type I procollagen and fibronectin also occurred but without a net increase in the rate of transcription of either of these genes. The preferential stabilization of mRNAs specifying type I procollagen and fibronectin provides a partial explanation for the mechanisms by which TGF beta enhances the synthesis of type I procollagen and fibronectin in mesenchymal cells.

Collagen↗
PubMed1985

Establishment of basal cell carcinoma in culture: evidence for a basal cell carcinoma-derived factor(s) which stimulates fibroblasts to proliferate and release collagenase.

The connective tissue adjacent to basal cell carcinomas (BCC) is frequently abnormal and contains increased numbers of fibroblasts and increased extractable collagenase. To determine whether BCC could produce these alterations by releasing mediators that regulated fibroblast function, we established BCC in culture and tested the ability of their culture supernatants to alter fibroblast proliferation and production of collagenase. Using tissue culture plates coated with type IV collagen and containing x-irradiated 3T3 feeder cells, we established epithelial colonies from 47% of the BCC cultured. The BCC-derived colonies differed from normal epidermal cell colonies in their morphology, growth rate, and keratin production. Culture supernatants from 4 out of 5 confluent BCC-derived colonies contained factors that stimulated fibroblasts to proliferate and release collagenase. These findings show that BCC-derived epidermal cell colonies release mediators which alter fibroblast functions and suggest that some of the connective tissue changes associated with BCC in vivo are the result of BCC-fibroblast interactions.

Aged↗
PubMed1984

Induction of fibroblast proliferation by interleukin-1 derived from human monocytic leukemia cells.

Human interleukin-1 (IL-1), free of contaminating lymphokines, was isolated from cultures of purified monoblasts from a patient with acute monocytic leukemia. Partially purified IL-1 (diafiltration, ultrafiltration, and isoelectric focusing) stimulated proliferation of subconfluent human fibroblasts in vitro. Further purification of IL-1 by high-resolution gel filtration- and anion exchange-high performance liquid chromatography revealed that fibroblast proliferation activity could not be separated from IL-1 activity (thymocyte proliferation), suggesting that both activities are the properties of a single molecule. Fibroblasts and thymocytes exhibited a similar sensitivity to the proliferative effects of IL-1. These findings suggest that macrophages participating in inflammatory reactions in vivo might release IL-1, which could function to expand fibroblast populations at sites of inflammatory reactions, by acting as a fibroblast growth factor.

Cell Division↗
PubMed1984

Lymphocyte modulation of fibroblast function in vitro: stimulation and inhibition of collagen production by different effector molecules.

Increased collagen deposition is a common feature of granulomatous and nongranulomatous inflammation associated with certain types of cell-mediated immune reactions in vivo. In the present study, we found that normal human peripheral blood mononuclear leukocytes cultured in vitro and stimulated by antigens or T cell mitogens release a 100 to 170 K m.w., heat-labile, trypsin-sensitive protein that stimulates dermal fibroblasts to produce increased quantities of type I and III collagens. Our data suggest that this collagen production protein is of T lymphocyte origin and that it preferentially stimulates production of collagen. We also observed that human mononuclear leukocytes release a different effector molecule with an m.w. of 55 K that inhibits fibroblast collagen production. Mononuclear leukocytes in culture are capable of releasing both the stimulator and the inhibitor of collagen production. The relative amounts of each of these factors elaborated by mononuclear leukocytes in culture appear to be influenced by several variables, such as cell density, type of stimulant used, and the duration of the culture period. These observations suggest that collagen production by fibroblasts in close proximity to sites in vivo where cell-mediated immune reactions are occurring might be regulated by both of these effector molecules.

Cell Division↗
PubMed1984

Protease inhibition of natural killer (NK) and antibody-dependent cell-mediated cytoxicity (ADCC) activities.

The ability of protease inhibitors to modulate NK and ADCC cell activities was studied. NK and ADCC cell activities were suppressed by 1,10 phenanthroline (PHE), N-alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK), L-1-tosylamide-2-phenylethylchoromethyl ketone (TPCK), N-benzoyl-DL-tyrosine ethyl ester (BTEE), and phenylethylchoromethyl fluoride (PMSF). The effect of these protease inhibitors on ADCC was not mediated through the early phase of cytotoxicity involving Fc-receptor binding, since they failed to alter EoxA rosetting of effector cells. The results suggest that an activated esterase system might play a role in the later phase of the cytotoxic mechanism by ADCC cells and perhaps NK cells.

Animals↗
PubMed1983

Interleukin 1 stimulation of collagenase production by cultured fibroblasts.

Interleukin 1 is a monokine that exerts biological effects on a variety of target cells in vitro. In this report, interleukin 1 has been found to be capable of stimulating collagenase production by cultured dermal fibroblasts. The concentrations of interleukin 1 that stimulate fibroblast collagenase production are similar to those that stimulate mouse thymocyte proliferation. Analyses by high performance liquid chromatography indicate that interleukin 1, rather than a contaminating monokine, is responsible for this effect on fibroblasts. Interleukin 1, released in vivo by macrophages infiltrating sites of tissue damage or inflammation, may function to stimulate the release of collagenase by connective tissue fibroblasts.

Chromatography, High Pressure Liquid↗
PubMed1983

Alterations in collagen production in mixed mononuclear leukocyte-fibroblast cultures.

The cell-cell interactions between fibroblasts and mononuclear leukocytes (MNL) which promote alterations in collagen accumulation were examined using a system of co-culture of human fibroblasts and peripheral blood MNL. The stimulation of collagen production was optimal after 48 h of co-culture and the increase in collagen correlated directly with the number of MNL added. The enhancement of collagen production was seen in both autologous and allogeneic co-cultures. Stimulation of non-collagenous protein was also noted. Co-culture supernatants contained soluble substances that were capable of stimulating collagen production, although they stimulated collagen production to a lesser degree than direct co-culture. Fractionation of these supernatants on Sephadex G-200 revealed a predominant area of stimulatory activity at 160,000 mol wt. Lesser areas of activity were noted at molecular weights of 80,000 and 25,000. Determination of the types of collagen produced by fibroblasts during co-culture with MNL showed that the ratio of type I:III collagen was decreased. These alterations in both the quantitative and qualitative accumulation of collagen mimic the changes often seen in wound healing and early inflammation suggesting that cellular interactions between fibroblasts and MNL may be important in the modulation of collagen production in normal and pathologic states.

Cells, Cultured↗