Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.2.1.36 (hyaluronidase)
4,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We characterized the mechanisms by which recombinant (r) tumor necrosis factor (TNF), IFN-gamma, and IL-1, alone and in combination, regulate human lung fibroblast hyaluronic acid (HA) production. Each cytokine stimulated fibroblast HA production. The combination of rTNF and rIFN-gamma resulted in a synergistic increase in the production of high molecular weight HA. This was due to a synergistic increase in hyaluronate synthetase activity and a simultaneous decrease in HA degradation. In contrast, when rTNF and rIL-1 were combined, an additive increase in low molecular weight HA was noted. This was due to a synergistic increase in hyaluronate synthetase activity and a simultaneous increase in HA degradation. Human lung fibroblasts contained a hyaluronidase that, at pH 3.7, depolymerized high molecular weight HA to 10-40 kD end products of digestion. However, hyaluronidase activity did not correlate with fibroblast HA degradation. Instead, HA degradation correlated with fibroblast-HA binding, which was increased by rIL-1 plus rTNF and decreased by rIFN-gamma plus rTNF. Recombinant IL-1 and rTNF weakly stimulated and rIL-1 and rTNF in combination further augmented the levels of CD44 mRNA in lung fibroblasts. In contrast, rIFN-gamma did not significantly alter the levels of CD44 mRNA in unstimulated or rTNF stimulated cells. These studies demonstrate that rIL-1, rTNF, and rIFN-gamma have complex effects on biosynthesis and degradation which alter the quantity and molecular weight of the HA produced by lung fibroblasts. They also show that fibroblast HA degradation is mediated by a previously unrecognized lysosomal-type hyaluronidase whose function may be regulated by altering fibroblast-HA binding. Lastly, they suggest that the CD44 HA receptor may be involved in this process.
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PMID:Cytokine regulation of human lung fibroblast hyaluronan (hyaluronic acid) production. Evidence for cytokine-regulated hyaluronan (hyaluronic acid) degradation and human lung fibroblast-derived hyaluronidase. 140 Oct 82

An improved micro method for measuring sulfated glycosaminoglycans (S-GAG) in chondrocyte cultures using 1,9-Dimethylmethylene Blue (DMB) has been developed. By increasing the protein concentration in the DMB assay a soluble GAG-DMB complex is prolonged. Without bovine serum albumin (BSA) in the phosphate-buffered saline (PBS) medium, the half time for loss of absorbance was 18 min; with 1% BSA-PBS there was no loss of absorbance over this time period. The limit of detection in a 96 well microtiter plate assay was 2 micrograms/ml; for a cuvette assay it was 1 microgram/ml. Collagen, DNA and RNA did not interfere with this assay. Hyaluronate caused an increase in absorbance at 530 nm that was lost by preincubating with Streptomyces hyaluronidase. The increase in absorbance was due to a turbidity change because there was no color shift from 600 to 530 nm but rather a uniform increase in absorbance between 400 to 700 nm. To validate the assay, the S-GAG was measured in conditioned medium from primary bovine articular chondrocyte monolayer cultures. A protein synthesis inhibitor, cycloheximide, blocked proteoglycan synthesis by greater than 90%. A cytokine, Interleukin-1 alpha, caused a dose-dependent decrease in proteoglycan accumulation. Chondroitinase ABC digestion of the chondrocyte conditioned medium completely prevented reactivity with the DMB. By preincubating samples with specific enzymes, different types of S-GAG can be measured with this assay. This assay can be used to measure changes in proteoglycans synthesized by chondrocytes.
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PMID:An improved method for determining proteoglycans synthesized by chondrocytes in culture. 237 28

The effect of sodium hyaluronate on the production of migration inhibitory factor (MIF) was studied in a two step MIF-assay. High molecular weight sodium hyaluronate (100 micrograms/ml), added during the inductory step of the MIF-assay, inhibited the production of MIF. The inhibitory effect did not appear to be due to physical factors such as steric hindrance, which may prevent mitogen binding, since cells preactivated with phytohemagglutinin A (PHA) did not produce MIF when incubated in the presence of sodium hyaluronate. The inhibitory effect was still measurable when the sodium hyaluronate was added upto two hours after stimulation of the mononuclear cells with PHA. Inhibition was also found when the cells were preincubated with sodium hyaluronate, and washed prior to mitogen stimulation. Sodium hyaluronate could only be removed from the cells by incubation with hyaluronidase or by incubation of the cells for at least two hours in culture medium, whereafter the cells could be stimulated to the same extent as normal untreated cells to produce MIF. This inhibitory effect on cytokine production may explain the reduced inflammatory reactions found both in vivo and in vitro in the presence of sodium hyaluronate.
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PMID:The influence of high molecular weight sodium hyaluronate (Healon) on the production of migration inhibitory factor. 332 86

Leukoregulin, a 50-kDa glycoprotein lymphokine, can regulate the extracellular matrix in dermal fibroblasts. Here we investigate the effects of leukoregulin on the synthesis of glycosaminoglycans in human orbital fibroblasts. We demonstrate that leukoregulin enhances the incorporation of [3H]glucosamine into glycosaminoglycans. The effect is dose dependent in the concentration range tested (0.1-2 U/ml), is maximal at 1 U/ml, and is time dependent. [3H]glycosaminoglycan accumulation is enhanced 7.67 +/- 1.23-fold (SE, n = 7) in orbital fibroblast strains. Pulse-chase studies indicate that this enhanced accumulation is not a result of a decreased rate of macromolecular degradation. Radiolabeled material induced by leukoregulin is sensitive to Streptomyces hyaluronidase digestion. Dexamethasone (10(-8) M) and cycloheximide (10 micrograms/ml) can block the cytokine's stimulation of hyaluronan synthesis. [35S]sulfate incorporation into glycosaminoglycan is unaffected by leukoregulin. In dermal fibroblasts, leukoregulin increased hyaluronan synthesis 3.66 +/- 0.37-fold (n = 5 strains, P < 0.02 compared with orbit). The increase in hyaluronan synthesis in orbital fibroblasts is substantially greater than that observed previously with other cytokines, making leukoregulin a candidate molecular trigger in Graves' ophthalmopathy.
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PMID:Leukoregulin is a potent inducer of hyaluronan synthesis in cultured human orbital fibroblasts. 786 77

Increasing evidence suggests that cytokine products of the immune system may play a regulatory role in corpus luteum regulation in several species. The role of cytokines in primate luteal function, however, remains unclear. In the present study we examined the effects of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), and interferon-gamma (IFN-gamma) on progesterone and prostaglandin (PGE2, PGF2 alpha) production by primate luteal cells in vitro. Specifically, corpora lutea were removed from normally cycling cynomolgus monkeys (n = 30 corpora lutea) during either the early (Days 3-5 after the estimated LH surge), mid (Days 8-10), or late (Days 12-14) luteal phase of the menstrual cycle. The corpora lutea were dispersed into individual cells using collagenase, DNase, and hyaluronidase. Approximately 50,000 viable luteal cells per tube were incubated in Ham's F-10 medium with increasing concentrations of IL-1 beta (0.1-10 ng/ml), TNF alpha (1-100 ng/ml), or IFN-gamma (10-1000 U/ml) in the presence and absence of hCG for 8 h at 37 degrees C. TNF alpha and IFN-gamma had no effect on progesterone PGE2, or PGF2 alpha production during any phase of the cycle at the doses tested. In contrast, IL-1 beta significantly stimulated PGF2 alpha production in a dose-dependent manner during the mid and late luteal phases (p < 0.05). Human CG alone had no effect on PGE2 or PGF2 alpha production by dispersed luteal cells in vitro but inhibited IL-1 beta-stimulated PGF2 alpha production. As expected, hCG stimulated progesterone production by primate luteal cells in vitro. Interestingly, IL-1 beta inhibited this hCG stimulation of progesterone production. In summary, these date suggest that IL-1 beta is a potentially important modulator of prostaglandin production by the primate corpus luteum. In view of this, cytokine-mediated changes in prostaglandin production by the primate corpus luteum may participate in the physiological regulation of luteal function.
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PMID:Interleukin-1 beta modulates prostaglandin and progesterone production by primate luteal cells in vitro. 904 11

Previous studies have indicated that fetal skin fibroblasts display an elevated level of migratory activity compared to adult cells and that this may result from inherent differences in the production of hyaluronan (HA) by these cells. Data presented in this communication indicate that the elevated level of fetal fibroblast migration into 3D-collagen gels and HA synthesis by these cells were not affected by epidermal growth factor (EGF), platelet-derived growth factor (PDGF), acidic fibroblast growth factor (aFGF) or basic fibroblast growth factor (bFGF). In contrast, both cell migration and HA synthesis by fetal fibroblasts were inhibited by transforming growth factor-betal (TGF-beta1). Adult fibroblasts responded to these cytokines in a distinct fashion: i.e. cell migration and HA synthesis were stimulated by EGF, PDGF, aFGF and bFGF, but remained unaffected by TGF-beta1. Gel-filtration chromatography revealed that these effects of cytokines on HA synthesis were predominantly confined to the production of high molecular mass (>106 kDa) species. Co-exposure of cells to both cytokines and Streptomyces hyaluronidase revealed that (1) the elevated migration of control fetal fibroblasts was inhibited by hyaluronidase, (2) this inhibition was partially restored by co-exposure to EGF, PDGF, aFGF and bFGF, but remained unaffected by TGF-beta1, (3) the migration of control adult fibroblasts was unaffected by hyaluronidase and partially stimulated by EGF, aFGF and bFGF (when compared to the effects of these cytokines on cells cultured in the absence of hyaluronidase) and (4) neither PDGF nor TGF-beta1 affected the migration of hyaluronidase-treated adult cells. Linear regression analysis revealed a significant correlation between cell migration and HA synthesis by both fetal and adult fibroblasts in the presence and absence of cytokines (r2=0.9277, P<0.0001), with the exception of adult fibroblasts exposed to PDGF. Taken together, these findings suggest that (1) the migration of fetal and adult fibroblasts is differentially modulated by exogenous cytokines and (2) with the possible exception of the effects of PDGF on adult fibroblasts, cytokine-induced modulation of cell migration appears to utilise both HA-dependent and HA-independent pathways.
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PMID:Differential response of fetal and adult fibroblasts to cytokines: cell migration and hyaluronan synthesis. 910 75

The physiological inflammatory response can provide an effective mechanism for delivering the baby at the time of parturition. We characterized the mechanisms by which hyaluronic acid (HA) regulates interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interleukin-8 (IL-8) production in human uterine fibroblasts. A dose-dependent increase in cytokine release was observed over an HA concentration range of 10 microg/ml to 1 mg/ml. The action of HA on the cytokine production is mediated by CD44. Under serum-free conditions, HA-induced cytokine generation was significantly less compared with production in the presence of serum, suggesting involvement of serum proteins. Addition of inter-alpha-trypsin inhibitor (ITI) under serum-free conditions enhanced the HA-induced synthesis of TNF-alpha, which stimulated the temporary release of IL-8. In addition, HA and IL-1beta stimulated the release of hyaluronidase by the fibroblasts. These results indicate that cytokine production in human uterine fibroblasts is regulated in a CD44-HA-ITI-specific fashion. HA may be involved in the regulation of delivery in part through the selective release of cytokines that contribute to uterine cervical ripening.
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PMID:Hyaluronic acid-specific regulation of cytokines by human uterine fibroblasts. 935 58

The glycosaminoglycan hyaluronan is an important component of the extracellular matrix of articular cartilage, contributing to both the structural and functional integrity of this highly specialized tissue. Hyaluronan is known to be synthesized and turned over by the resident chondrocytes, although the mechanisms involved in hyaluronan degradation are not precisely defined. Recently, the cDNA sequences of extracellular hyaluronidases present on spermatazoa and in human serum have been reported, and we have utilized these data to investigate the expression and activity of these and/or related enzymes by articular cartilage chondrocytes. By using "gene-homology" RT-PCR techniques, three hyaluronidase isozymes were found to be expressed by chondrocytes, and hyaluronidase activity was detected in cell membrane extracts and conditioned media from chondrocyte monolayer cultures following acidification to pH 4.5 or pH 3.7. In addition, the levels of mRNA for two of the chondrocyte hyaluronidases were upregulated by IL-1 and TNF stimulation, thereby implicating cartilage-derived hyaluronidase activity as a factor contributing to cytokine-induced extracellular matrix degradation during synovial joint disease.
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PMID:Expression and activity of articular cartilage hyaluronidases. 979 Sep 94

The glycosaminoglycan hyaluronate (HA) is part of the extracellular environment in bone marrow. We show here that HA activates signal transduction cascades important for hemopoiesis. In myeloid and lymphoid long-term bone marrow cultures (LTBMC), treatment with hyaluronidase (HA'ase) results in reduced production of both progenitor and mature cells. Exogeneous HA added to LTBMC had the opposite effect: it enhanced hematopoiesis. The effect of HA is mediated through two different HA receptors on bone marrow macrophage-like cells, one of which is CD44 while the other is unknown. HA induces bone marrow macrophages to secrete IL-1beta (CD44-dependent) and IL-6 (CD44-independent). The two receptors address different signal transduction pathways: CD44 links to a pathway activating p38 protein kinase while the other yet unknown receptor induces Erk activity. There was no difference of the effect of HA and HA'ase on hematopoiesis in LTBMC and on cytokine production by macrophages in CD44-deficient mice compared with wild-type mice, indicating that the CD44 hyaluronate receptor and its signal transduction can be compensated for. Our data suggest a regulatory role for the extracellular matrix component HA in hematopoiesis and show the induction of signal transduction by HA receptors.
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PMID:Hyaluronate-enhanced hematopoiesis: two different receptors trigger the release of interleukin-1beta and interleukin-6 from bone marrow macrophages. 1041 85

We have recently demonstrated that the three principal mammalian isoforms of transforming growth factor beta (TGF-beta) exert distinct effects upon: (1) the migration of confluent adult fibroblasts into 3D gels of native type I collagen fibres (i.e. TGF-beta-1 and -2 had no apparent motogenic activity, whilst TGF-beta-3 induced a dose-dependent stimulation of cell migration); and (2) the synthesis of hyaluronan (HA) by these cells is also affected by the TGF-beta isoforms in a manner which parallels their effect on cell migration. The objective of the present study is to elucidate the manner in which this differential activity of the TGF-beta-1, -2 and -3 may be modulated by experimental parameters. Data presented in this communication indicate that cytokine bioactivity is determined by a combination of cell density and the nature of the macromolecular substratum. Thus, we now report that all three TGF-beta isoforms inhibit the migration of subconfluent cells in the collagen gel assay. Our data confirm that the migration of confluent cells is stimulated by TGF-beta-3 and further indicate that this motogenic activity is completely abrogated by either TGF-beta-1 or -2 when these are co-incubated with TGF-beta-3. In contrast to these results obtained using a native type I collagen substratum, all three isoforms stimulated adult fibroblast migration in the transmembrane assay (in which cells are adherent to a 2-D porous polycarbonate substratum). The precise effect of TGF-beta isoforms on HA synthesis was also affected by cell density and the nature of the substratum in a manner which paralleled their diverse effects on cell migration (i.e. stimulation, inhibition or no effect). Streptomyces hyaluronidase completely neutralized the TGF-beta-3-induced stimulation of confluent fibroblast migration, thus suggesting a mechanistic link between the cytokine-induced cell migration and HA synthesis under these conditions. Taken together, these data indicate that: (1) the bioactivity of TGF-beta-1, -2 and -3 are determined by cell density, the macromolecular substratum and the presence of other cytokines; and (2) it is therefore necessary to define cytokine bioactivity within the context of a larger 'tissue response unit' which more fully defines the activity state of the target cell and its microenvironment.
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PMID:Motogenic and biosynthetic response of adult skin fibroblasts to TGF-beta isoforms (-1, -2 and -3) determined by 'tissue response unit': role of cell density and substratum. 1072 70


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