Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:031673 (collagen)
 124,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To extravasate into normal and neoplastic tissue, lymphocytes must migrate through the subendothelial basement membrane and underlying interstitium, structures rich in extracellular matrix (ECM). We have performed a time-course study of the development of motility in ECM by murine lymphocytes during in vitro exposure to high titers of IL-2 (1000 Cetus units/ml). This protocol generates immunotherapeutic lymphocyte populations expressing lymphokine-activated killer activity. Spontaneous motility was measured in three-dimensional gels of type I (interstitial) collagen or Matrigel, a model basement membrane. A newly developed assay permitted not only the measurement of distance traveled by the leading cell front, but also the separation of lymphocytes on the basis of three types of behavior. The motile fraction consisted of lymphocytes that penetrated beneath the ECM gel surface during an 18-h migration period. There were also two nonmotile fractions: the nonadherent fraction, which failed to bind to the gel surface; and the adherent fraction, which bound but did not penetrate during the assay period. During a 3- to 5-day exposure to high titer IL-2, both adherence and motility increased significantly. In type I collagen, cells of the NK lineage developed greater surface adherence and less motility than cells of the T lineage. The surface-adherent fraction expressed higher lymphokine-activated killer and NK activity than did the nonadherent or motile fractions. Under prolonged IL-2 stimulation (7 to 12 days), there was a decline in the percentage of cells exhibiting motility in both types of ECM, and an increase in the percentage of surface-adherent cells. The findings indicate that the behavior of an IL-2-stimulated lymphocyte population in ECM is profoundly influenced by the duration of IL-2 exposure. Furthermore, lack of lymphocyte motility may reflect two different behaviors, nonadherence and adherence without motility. The nonadherent and surface-adherent populations may differ in phenotypic distribution and function. The motility system described in this report will be useful in separating and studying the mechanisms that produce lymphocyte adherence and motility, and in understanding the in vivo implications of these behaviors.
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PMID:Lymphocyte development of adherence and motility in extracellular matrix during IL-2 stimulation. 138 7

During inflammation and recirculation, lymphocytes migrate into tissues by traversing the capillary endothelium, a process known as extravasation. After crossing the endothelial cells, lymphocytes come into contact with the basement membrane, which is a specialized layer of extracellular matrix containing predominantly laminin, collagen type IV, entactin, and heparan sulfate proteoglycans. In tissue invasion by inflammatory cells and metastatic tumor cells, the basement membrane serves as a substratum for cell adhesion and migration. However, the role of basement membrane in lymphocyte extravasation remains unclear. In this study, we investigated the effect of basement membrane on lymphocyte adhesion, migration, and proliferation, using matrigel as a model for basement membrane. We observed that matrigel promotes both lymphocyte adhesion and migration, with entactin primarily responsible for promoting adhesion and laminin for promoting migration. In addition, activation of lymphocytes by anti-CD3 enhances their adhesion and migration on matrigel-coated substratum. We also observed that matrigel inhibits the proliferation of lymphocytes stimulated by Con A. Furthermore, we demonstrated that laminin is the matrigel component responsible for inhibiting lymphocyte proliferation. However, matrigel has no effect on the proliferation of lymphocytes stimulated by LPS. These results suggest that matrigel has different effects on lymphocyte subpopulations. In agreement with the results on proliferation, matrigel also inhibits the production of IL-2 by Con A-stimulated lymphocytes.
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PMID:Basement membrane and its components on lymphocyte adhesion, migration, and proliferation. 143 Oct 96

A synthetic chimeric IL-2/IL-6 gene was synthesized to engineer a bifunctional lymphokine which was overproduced in Escherichia coli. Following denaturation of the inclusion bodies in 6 M guanidine and refolding and reoxidation in the presence of a redox system, the fusion protein (rIL-2/IL-6) was purified to homogeneity and shown to react with both monospecific anti-IL-2 and anti-IL-6 antisera. A collagen-like spacer was introduced between the two cytokine moieties to generate IL-2 and IL-6 molecules upon collagenase digestion. After cleavage, the two subunits, purified in a single-step procedure, were found to be correctly reoxidized and functionally as active as their native counterparts. Circular dichroism studies of rIL-2/IL-6 revealed that both cytokine subunits refolded independently and exhibited the alpha-helical structures characteristic of the corresponding wild-type lymphokines. The chimera displayed full IL-2 activity in the CTLL-2 cell proliferation assay. It also retained the IL-6 property to enhance IgM synthesis in SKW6.4 cells, induce the proliferation of B-cell hybridomas and stimulate the production of fibrinogen in hepatocytes. Because IL-2 amplifies the cellular immune response and IL-6 up-regulates the humoral response, this bifunctional lymphokine represents a potentially useful therapeutic adduct and may serve as an immunomodulator to enhance the host's response to vaccination.
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PMID:Overexpression and structure--function analysis of a bioengineered IL-2/IL-6 chimeric lymphokine. 143 70

The effects of glioma culture supernatant (GCS) and interleukin-2(IL-2) on the motility of autologous stimulated lymphocytes (ASL) were studied by using collagen gel system, chemotaxic chamber system and flow cytometric analysis. GCS inhibited the migration of ASL into collagen gel. It enhanced the ASL motility and the expression of CD 26 antigen on the cell surface. IL-2 inhibited the migration of ASL into collagen gel and had no influence on the motility of ASL, but enhanced the expression of CD 26 antigen. On the other hand, a clinical glioma specimen showed limited depth of ASL migration when injected into the tumor cavity in addition to the formation of fibrin like membrane on its surface and a layer of degenerated ASL under it. To make ASL therapy more effective to malignant glioma, the following measures should be recommended; 1) inject adequate volume of IL-2 into tumor cavity, 2) reduce the frequency of ASL administration, 3) wash out of glioma secreting factors, degenerated ASL and glioma cells in addition to reduce the volume of tumor tissue.
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PMID:[The motility of IL-2 activated lymphocytes into malignant glioma]. 147 10

Fibroblasts in parenchymal organs potentially contribute extracellular matrix to local fibrogenic processes. This contribution, in some circumstances, may be initiated by cytokines disseminated from inflammatory lesions. Different populations of fibroblasts, however, might respond distinctively to this cytokine bath depending on the microenvironment in which they reside. We have begun to explore this issue using syngeneic, low-passage fibroblasts cultured in serum-free media that were derived originally from the dermis (DFBs) and from tubulointerstitium (TFBs) of the kidney. Our findings indicate that, while fibroblasts from each compartment appear similar at the ultrastructural level, there are a variety of functional differences which distinguish their proliferative response, and their collagen secretory response (types I, III, IV, and V) following challenge with various doses of immune-relevant cytokines (TGF beta, EGF, IL-1, IL-2 and gamma IFN) in culture. DFBs, for example, express more surface EGF receptors than do TFBs, and, as a consequence, exhibit a more robust proliferative response to EGF in serum-free media. Unstimulated DFBs also secrete more collagen types I and III than TFBs, while unstimulated TFBs secrete more types IV and V. The expression of these collagens in TFBs was confirmed by Northern blot hybridization. When these sets of fibroblasts were further stimulated by cytokines, some of the cytokines not only differentially effect the secretion of various species of collagens within the same group of cells, but also between cells from populations which are anatomically distinct. DFBs, furthermore, at mid-level doses of cytokine, demonstrated a general trend towards less secretion of all types of collagen (particularly for TGF beta, EGF, and IL-2), while TFBs seemed less repressive. In TFBs the cytokine-induced responses for collagen types I and III tended to be discordant, and for types I and IV EGF inhibited, while TGF beta stimulated the secretory process. These findings speak collectively for the presence of a functional heterogeneity among organ-based populations of syngeneic fibroblasts in normal tissues.
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PMID:Biosynthetic and proliferative characteristics of tubulointerstitial fibroblasts probed with paracrine cytokines. 159 50

Mice immunized with human collagen IV develop either antibody responses or T-cell proliferative responses as a function of the MHC genotype of the immunized mice. CD4+ T cells, similar to Th1 and Th2 cells, participate in these two types of responses, with CD4+ T-cell proliferative responses associating with IL-2 and IFN gamma release, and antibody production associating with CD4+ T-cell IL-4 and IL-5 release. Thus it would appear that the same antigen can induce responses consistent with either cell-mediated or humoral immunity depending on MHC class II genotype. In attempting to understand how MHC genotype controls the class of immunity observed several models are discussed. It was proposed, based on results obtained upon priming with human collagen IV, that the activation of Th1 and Th2 responses may be regulated at several levels (presentation by different APCs, presentation of different densities of the T-cell receptor ligand and presentation of different T-cell epitopes). With the identification of the peptide recognized by the CD4+ T cells, it was clear that the inability to induce Th1 responses in H-2b and the inability to induce Th2 responses in H-2s could not be accounted for by the failure to generate an immunodominant peptide during processing or the failure of the peptides to bind to the MHC class II molecules. Furthermore, the difference in the type of response generated could not be explained by the use of different peptides of the human collagen IV molecule in the two mouse strains, as a single peptide will induce both types of CD4+ T-cell response. However, it cannot be ruled out that the a2 peptide-class II interaction forms different T-cell ligands in the two strains either because the two class II MHC molecules are different or that the peptide is processed and reveals a different antigenic activity (Fox et al. 1988). Perhaps the most important finding from the peptide studies is that the lack of proliferative response in H-2b mice is not absolute, but can be overcome either by priming with high doses of the a2 peptide or by increasing the amount of peptide needed to elicit a recall response. It seems reasonable to speculate that changes in the dose required for priming Th1 or Th2 responses may reflect differences in the activation requirements of the two types of cells with Th1 cells requiring a high ligand density and Th2 cells a low ligand density.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Selective activation of Th1- and Th2-like cells in vivo--response to human collagen IV. 168 84

The capacity of purified fibronectin to costimulate human T cell DNA synthesis was examined. Low concentrations of immobilized fibronectin, but not soluble fibronectin, augmented anti-CD3-induced proliferation of highly purified human T cells. In the absence of anti-CD3 stimulation, immobilized fibronectin did not induce T cell proliferation alone or in the presence of IL-2 or phorbol dibutyrate. Although fibronectin is present in high concentrations in the serum, immobilized fibronectin was able to costimulate T cell proliferation when cells were cultured in serum-containing medium. Immobilized collagen type I did not enhance anti-CD3 stimulated T cell responses, whereas gelatin (denatured collagen) and laminin were able to enhance anti-CD3 stimulated T cell responses modestly. The effects of gelatin, however, appeared to be indirect, because it could not enhance responses in medium devoid of fibronectin. Immobilized fibronectin enhanced anti-CD3 induced proliferation of both CD45RA dim and CD45RA bright subsets within both the CD4+ and CD8+ subpopulations of T cells, although cells with the CD45RA dim phenotype were costimulated by lower concentrations of immobilized fibronectin. Enhancement of anti-CD3 induced proliferation by immobilized fibronectin was completely inhibited by a mAb to CD29, the integrin beta 1-chain (4B4) and not by a variety of other mAb. In contrast to its effects on proliferation, 4B4 only partially blocked T cell binding to anti-CD3 and fibronectin-coated macrowells. These findings suggested that the interaction between fibronectin and its receptor transduced a signal to the T cell and did not merely stabilize the interaction between anti-CD3 and the CD3 complex. Further experiments confirmed this observation. Thus fibronectin could enhance anti-CD3 responses when it was immobilized to a separate surface. The augmentation of anti-CD3 stimulated proliferation induced by immobilized fibronectin was also inhibited partially by mAb to either VLA-4 or VLA-5 and completely by a combination of the two mAb. The mAb to VLA-4 not only blocked the capacity of immobilized fibronectin to enhance anti-CD3-induced T cell proliferation but also directly costimulated T cell responses. Thus, at least two fibronectin receptors are involved in fibronectin-mediated costimulation of T cell proliferation. These studies indicate that signals are transduced through the fibronectin receptors, VLA-4 and VLA-5, that augment T cell responses and therefore implicate the extracellular matrix protein fibronectin as an important influence regulating T cell responsiveness in vivo.
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PMID:Fibronectin promotes proliferation of naive and memory T cells by signaling through both the VLA-4 and VLA-5 integrin molecules. 169 44

Rat/mouse T-T hybridomas have been developed from an arthritogenic and a nonarthritogenic T cell line. These hybridomas express alpha beta TCR and are CD4+, CD8-, and MRC OX-22-. They have type II collagen reactivity as assessed by an IL-2 release assay. Southern blot analysis of DNA extracted from these hybridomas demonstrates that each T cell line contains at least three different collagen-reactive clones. The data suggest that the spectrum of TCR beta gene rearrangements is limited, as one hybridoma from the nonpathogenic line shares an identically sized productive TCR beta gene rearrangement with two hybridomas from the pathogenic line. Both cell lines as well as one hybridoma from the pathogenic line are autoreactive to rat type II collagen. The anti-collagen responses of all the hybridomas are restricted to the rat class II MHC RT1.B gene loci. The hybridomas, like their parental cell lines, do not respond preferentially to either native or denatured type II collagen. These hybridomas recognize a specific type II collagen epitope and not repetitive collagen-like sequence motifs. They require antigen processing to respond to both native and denatured type II collagen.
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PMID:Characterization of collagen-specific T cells derived from pathogenic and nonpathogenic rat T cell lines. 169 63

Eicosanoids, lymphokines, and free radicals are known to participate in the pathogenesis of inflammation. Tumour necrosis factor (TNF), interleukin-1 and 6 (IL-1 and IL-6) and colony stimulating factor -1 (CSF-1) are secreted mainly by activated macrophages, whereas T-cells secrete IL-2, IL-3, IL-4 and interferon-gamma (IFN-gamma). In addition, activated macrophages and lymphocytes can also produce eicosanoids and free radicals which have potent pro-inflammatory actions. Eicosanoids, lymphokines, and free radicals can modulate the immune response, cell proliferation, stimulate collagenase and proteases secretion and induce bone resorption; events which are known to be associated with various collagen vascular diseases. On the other hand transforming growth factor-beta (TGF-beta) produced by synovial tissue, platelets and lymphocytes can inhibit collagenase production, suppress T-cell and NK-cell proliferation and activation and block free radical generation and seems to be of benefit in rheumatoid arthritis. Drugs such as cyclosporine, 1,25,dihydroxycholecalciferol and pentoxyfylline can block lymphokine and TNF production and thus, may inhibit the inflammatory process. Essential fatty acids, the precursors of eicosanoids, are suppressors of T-cell proliferation, IL-1, IL-2 and TNF production and have been shown to be of benefit in rheumatoid arthritis, systemic lupus erythematosus and glomerulonephritis. Thus, the interactions between essential fatty acids, eicosanoids, lymphokines, TGF-beta and free radicals suggest that new therapeutic strategies can be devised to modify the course of collagen vascular diseases.
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PMID:Interaction(s) between essential fatty acids, eicosanoids, cytokines, growth factors and free radicals: relevance to new therapeutic strategies in rheumatoid arthritis and other collagen vascular diseases. 172 26

The nature of the fibrosis associated with mammary carcinomas MC2 and MC3 was investigated in syngeneic C3H mice. Accelerated and enhanced peri-tumor cellular and fibrotic responses and retarded tumor growth were observed in actively immunized and in adoptively immunized mice, and in mice treated with IL-2. T lymphocytes and, particularly, macrophages were closely associated with collagen deposition at the tumors. The collagen deposition frequently resulted in the encapsulation and regression of the less invasive tumor MC2. A cellular fibrous response was not observed at tumors implanted into athymic C3Hnu/nu mice. The results suggest that tumor fibrosis may in some circumstances be promoted by an immune response.
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PMID:Immunologic aspects of fibrosis in mouse mammary carcinomas. 172 15


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