Down-regulation of α3(VI) chain expression by γ-interferon decreases synthesis and deposition of collagen type VI (original) (raw)
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Transcriptional Control of Human Diploid Fibroblast Collagen Synthesis by ?-Interferon
Annals of the New York Academy of Sciences, 1985
Normal fibroblasts possess delicate regulatory mechanisms that permit the production of sufficient collagen to meet the demands of the extracellular matrix during dynamic processes such as development, differentiation, and repair. Abnormalities in collagen regulation may be responsible for the excessive fibrosis characteristic of certain diseases such as scleroderma. The close proximity of inflammatory cells with fibroblasts in areas of repair and early fibrosis suggests that inflammatory cells can regulate fibroblast function. Of the variety of factors produced by inflammatory cells, interferons (IFNs) have been some of the most extensively studied, but the possibility that they may modulate fibroblast collagen synthesis has not been investigated until recently.' In the present work we have studied the effects of recombinant y-IFN (rec y-IFN) on collagen synthesis, independently of its effects on fibroblast proliferation, employing confluent dermal fibroblasts.
Differential and restricted expression of novel collagen VI chains in mouse
Matrix Biology, 2011
Recently, three novel collagen VI chains, α4, α5 and α6, were identified. These are thought to substitute for the collagen VI α3 chain, probably forming α1α2α4, α1α2α5 or α1α2α6 heterotrimers. The expression pattern of the novel chains is so far largely unknown. In the present study, we compared the tissue distribution of the novel collagen VI chains in mouse with that of the α3 chain by immunohistochemistry, immunoelectron microscopy and immunoblots. In contrast to the widely expressed α3 chain, the novel chains show a highly differential, restricted and often complementary expression. The α4 chain is strongly expressed in the intestinal smooth muscle, surrounding the follicles in ovary, and in testis. The α5 chain is present in perimysium and at the neuromuscular junctions in skeletal muscle, in skin, in the kidney glomerulus, in the interfollicular stroma in ovary and in the tunica albuginea of testis. The α6 chain is most abundant in the endomysium and perimysium of skeletal muscle and in myocard. Immunoelectron microscopy of skeletal muscle localized the α6 chain to the reticular lamina of muscle fibers. The highly differential and restricted expression points to the possibility of tissue-specific roles of the novel chains in collagen VI assembly and function.
Matrix Biology, 1998
Previous studies have shown that interferon-7 (IFN-7) inhibits type I collagen gene expression through both transcriptional and post-transcriptional mechanisms (K/ih/iri et al., 1990). In the present study, using transient cell transfections of human dermal fibroblast cultures with a series of 5' deletion promoter/CAT reporter gene constructs, we have identified the IFN-7-response element of the human ct2(I) collagen gene (COL1A2) promoter. Specifically, we have identified a segment of the proximal promoter region, located between nucleotides-161 and-125 relative to the transcription start site, as critical for down-regulation of COLIA2 promoter activity by IFN-7. This IFN-7 response element (IgRE) is clearly distinct from the previously described tumor necrosis factor-cz response element (TARE) located between nucleotides-265 and-241 of the COLIA2 promoter, a difference which is likely to explain the additive inhibitory effect of these two cytokines. The inhibitory effect of IFN-7 was dose-dependent and rapidly induced, requiring less than 5 min exposure of fibroblast cultures. Gel mobility shift assays indicated that a highly specific nuclear protein complex bound to this 37-base pair region of promoter. Competition experiments with oligonucleotides spanning discrete segments of this promoter region mapped the binding element within a distinctive pyrimidine-rich sequence. Point mutations within the latter revealed that this element plays a crucial role not only in the IFN-7 response, but also in the basal activity of the proximal promoter. Substitution mutations within the IgRE of the-161/CAT construct attenuated the promoter response to IFN-7, as measured in transient cell transfections, and eliminated specific DNA/protein complex formation, as measured by gel mobility shift assay. UVcrosslinking experiments indicated that two DNA/protein complexes were formed with the IgRE, with molecular weights around 55 kDa and 30 kDa, corresponding to proteins of-30 kDa and-6 kDa, respectively. Our results further clarify the molecular mechanisms involved in the regulation of type I collagen gene expression by IFN-7.
Immunohistochemical Expression of Type VI Collagen in Superficial Fibromatoses
Pathology - Research and Practice, 1995
27 Werkmeister JA, Tebb TA, White JF, Ramshaw JA (1993) Monoclonal antibodies to type VI collagen demonstrate new tissue augmentation of a collagen-based biomaterial implant. J Histochem Cytochem. 41: 1701-1706 28 Zhang LQ, Laato M, Muona P, Kalimo H, Peltonen J (1994) Normal and hypertrophic scars: quantification and localization of messenger RNAs for type I, III and VI collagens. Br J Dermatol130: 453-459
Three Novel Collagen VI Chains, 4(VI), 5(VI), and 6(VI)
Journal of Biological Chemistry, 2008
We report the identification of three new collagen VI genes at a single locus on human chromosome 3q22.1. The three new genes are COL6A4, COL6A5, and COL6A6 that encode the ␣4(VI), ␣5(VI), and ␣6(VI) chains. In humans, the COL6A4 gene has been disrupted by a chromosome break. Each of the three new collagen chains contains a 336-amino acid triple helix flanked by seven N-terminal von Willebrand factor Alike domains and two (␣4 and ␣6 chains) or three (␣5 chain) C-terminal von Willebrand factor Alike domains. In humans, mRNA expression of COL6A5 is restricted to a few tissues, including lung, testis, and colon. In contrast, the COL6A6 gene is expressed in a wide range of fetal and adult tissues, including lung, kidney, liver, spleen, thymus, heart, and skeletal muscle. Antibodies to the ␣6(VI) chain stained the extracellular matrix of human skeletal and cardiac muscle, lung, and the territorial matrix of articular cartilage. In cell transfection and immunoprecipitation experiments, mouse ␣4(VI)N6-C2 chain co-assembled with endogenous ␣1(VI) and ␣2(VI) chains to form trimeric collagen VI molecules that were secreted from the cell. In contrast, ␣5(VI)N5-C1 and ␣6(VI)N6-C2 chains did not assemble with ␣1(VI) and ␣2(VI) chains and accumulated intracellularly. We conclude that the ␣4(VI)N6-C2 chain contains all the elements necessary for trimerization with ␣1(VI) and ␣2(VI). In summary, the discovery of three additional collagen VI chains doubles the collagen VI family and adds a layer of complexity to collagen VI assembly and function in the extracellular matrix. Collagen VI is an extracellular component that is present in virtually all connective tissues, where it forms abundant and structurally unique microfibrils in close association with basement membranes. Collagen VI interacts with a range of ECM 2 components. However, its precise role is not clearly understood. Several recent studies have suggested that collagen VI functions to anchor the basement membrane to the pericellular matrix in muscle (1-3). Other data suggest a role for collagen VI in cell signaling and cell migration (4, 5).
Purpose. has been shown to be a potent inhibitor of collagenous protein production independent of its effects on noncollagenous protein production and cell proliferation in vitro. To understand further the processes controlling tissue fibrosis and the potential use of 7-IFN as an antifibrotic treatment after glaucoma filtering surgery, the in vitro effects of recombinant 7-IFN on procollagen mRNA production were studied.
Archives of Dermatological Research, 1989
In order to determine whether interferons (IFNs) play a universal role in terminating the fibrotic response by inhibiting other fibroblast functions in addition to growth and collagen production, we investigated the effect of human recombinant (hu-r) IFNalpha, -beta, and -gamma on the glycosaminoglycan, fibronectin, and collagenase production of cultured human dermal fibroblasts. Our results show that shortterm (48 h) treatment of confluent fibroblast cultures with hu-r-IFN-alphaz and hu-r-IFN-beta-serl 7 causes a concentration (1 to 1 x l0 s U/ml)-dependent inhibition of glycosaminoglycan production, has no effect on fibronectin production, and markedly increases collagenase production. In contrast, hu-r-lFN-gamma not only causes a concentration-dependent increase in collagenase production but also increases both glycosaminoglycan and flbronectin production. These results demonstrate that IFNs differently regulate fibroblast functions rather than universally inhibit all functions, and show that IFN-alpha and -beta exhibit a broader antifibrotic spectrum that IFN-gamma.
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1988
The effects of intederon-a and intederon-T on collagen synthesis and mRNA levels of type I and type III procollagens were studied in skin fibroblasts cultured from affected and unaffected skin sites of two patients with localized scleroderma (morphea). Both scleroderma cell lines exhibited elevated type I and type III procollagen mRNA levels to account for the increased procollagen synthesis, when compared to the unaffected controls. Intederon-T treatment resulted in a dose-dependent reduction in collagen synthesis and procollagen mRNA levels in sderoderma fibroblasts. A 72-h exposure to interferon-,/ reduced procollagen mRNA levels in the scleroderma fibroblast lines to the levels exhibited by the unaffected control fibroblasts. The suppressive effect of intederon-a on procollagen mRNA levels was somewhat weaker than that of intederon-T. The results suggest potential use of interferon-y in treatment and prevention of human fibrotic conditions.