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Modulation of human dermal fibroblast extracellular matrix metabolism by the lymphokine leukoregulin



The effect of leukoregulin, a 50-kD lymphokine with unique antitumor properties, was studied in vitro on several fibroblast functions. Leukoregulin did not inhibit fibroblast proliferation, as measured by cell enumeration and [3H]thymidine incorporation, and had no cytotoxic effect in terms of increased membrane permeability detected by trypan blue exclusion, two of the major leukoregulin actions on tumor cells. Leukoregulin induced a dose-dependent decrease in collagen synthesis, demonstrated by decreased [3H]proline incorporation into collagenase- digestible protein, as early as 6 h after the addition of the lymphokine to human fibroblasts. Leukoregulin inhibited the synthesis of both type I and type III collagen, as measured by SDS-PAGE and by specific radioimmunoassay. Neutralizing antibodies to interleukin-1 alpha, interleukin-1 beta, tumor necrosis factor-alpha, and interferon- gamma failed to alter the effect of leukoregulin on collagen synthesis, attesting that leukoregulin action was not due to contamination by these cytokines. Inhibition of collagen synthesis occurred concomitantly with increased secretion of prostaglandin E2 and a transient rise in intracellular cyclic AMP content, peaking at 6 h. However, blocking prostaglandin synthesis with indomethacin did not counteract inhibition of collagen synthesis by leukoregulin, demonstrating independence of this action of leukoregulin from cyclooxygenase metabolites. Leukoregulin also stimulated glycosaminoglycan production in a dose-dependent manner, affecting the synthesis of hyaluronic acid as the major fibroblast-derived extracellular glycosaminoglycan. In addition, secretion of neutral proteases (collagenase, elastase, caseinase) was increased. These observations indicate that leukoregulin is able to regulate synthesis of molecules critical to the deposition of the extracellular matrix by nontransformed nonmalignant fibroblasts

Topics: Articles
Publisher: The Rockefeller University Press
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Provided by: PubMed Central

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  2. (1976). A novel assay for the biosynthesis of sulfated polysaccharide and its application to studies on the effects of somatomedln on cultured cells.
  3. (1977). A rapid and reproducible assay for collagenase using 1-x4C acetylated collagen.
  4. (1985). Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin F~ production by human synovial ceils and dermal flbroblasts.
  5. (1991). Comparative effects of interleukin-I and tumor necrosis factor-co on collagen production and corresponding mRNA levels in human dermal fibroblasts.
  6. (1988). Fibroblasts.
  7. (1987). Flow cytometric evaluation of leukoregulin as an intrinsic mediator of natural killer lymphocyte cytotoxicity. Lymphokine Res.
  8. (1988). Gene expression of fibroblMt matrix proteins is altered by indomethacin.
  9. (1988). Interleukin-1~ and ~l stimulate interlankin- 1 ~ gene expression in human dermal fibroblasts.
  10. (1988). Interleukin-lc~ modulates collagen gane expression in cultured synovial cells.
  11. (1987). Leukoregulin mechanisms of anticancer action.
  12. (1986). Leukoregulin-increased plasma membrane permeability and associated ionic fluxes. Cancer Res.
  13. (1985). Leukoregulin, a direct-acting anticancer immunological hormone that is distinct from iymphotoxin and interferon. Cancer Res.
  14. (1987). Modulation by recombinant interleukin 1 of synthesis of types I and HI collagens and associated procoilagen mRNA levels in cultured human cells.
  15. (1990). Modulation of human papilloma virus type 16 (HPV 16) early gene expression by TGF-/~I, "y-interferon (~/-IFN) and leukoregulin (LR).
  16. (1984). On the presence of a metalloprotease in human skin fibroblasts that degrades the human skin elastic fiber system.
  17. (1987). PGE2 causes a coordinate decrease in the steady state levels of fibronectin and types I and HI procollagan mRNAs in normal human dermal fibroblasts.
  18. (1989). Preparative isoelectric focusing in ampholine electrofocusing colums versus immobiline polyacrylamide gel for the purification of biologically active leukoregulin.
  19. (1975). Radioimmunoassay of prostaglandins F~,
  20. (1986). Regulation of fibroblast proliferation and collagen synthesis by cytokines, lmmunol.
  21. (1984). Selective inhibition of human diploid fibroblast collagen synthesis by interferons.
  22. (1981). Stimulation of rheumatoid synovial cells collagenase and prostaglandin production by partially purified lymphocyte activating factor (Interleukin-1).
  23. (1985). Stromelysin, a connective tissuedegrading metalloendopeptidase secreted by stimulated rabbit synovial fibroblasts in parallel with collagenase. Biosynthesis, isolation, characterization and subsu'ates.
  24. (1975). The effect of proteoglycans on the formation of fibrils from collagen solutions.
  25. (1987). The effect of transforming growth factor-13 on cell proliferation and collagen formation by lung fibroblasts.
  26. (1976). The estimation of two collagens from human dermis by interrupted electrophoresis.
  27. (1989). Transforming growth factor-~ regulation of collaganase, 72 kDa-progelatinase, TIMP and PAI-1 expression in rat bone cell populations and human fibroblasts.
  28. (1986). Transforming growth factor-13 stimulates the expression of flbronectin and collagen and their incorporation into the extracellular matrix.
  29. (1988). Tumor necrosis factor c~ inhibits collagen gene transcription and collagen synthesis in cultured human llbroblasts.
  30. (1990). Tumor necrosis factor-a and interferon-~ suppress the activation of human type I collagen gene expression by transforming growth factor-~l. Evidence for two distinct mechanisms of inhibition at the transcriptional and posttranscfiptional levels.
  31. (1988). Tumor necrosis factor-a inhibits collagen and fibronectin synthesis in human dermal fibroblasts. FEnS (Fed.
  32. (1986). Type I collagen production by human odontoblast-like cells in explatus cultured on cyanoacrylate films. Cell Tissue Res.
  33. (1971). Use of a mixture of proteinase-free coilagenases for the specific assay of radioactive collagen with presence of other proteins.

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