Differential regulation of the expression of proteinases/ antiproteinases in fibroblasts

Effects of interleukin-1 and platelet-derived growth factor

Antonella Circolo, Howard G. Welgus, Glenn F. Pierce, J. Krámer, Robert C. Strunk

Research output: Contribution to journalArticle

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Abstract

We have previously reported that polypeptide growth factors had an anti-inflammatory effect by decreasing the cytokine-enhanced expression of factor B (FB), an activator of the alternative complement pathway, in human fibroblasts. To further characterize the role of cytokines and growth factors in the inflammatory/repair continuum, we have studied the effects of interleukin-1 (IL-1) and platelet-derived growth factor (PDGF) on the expression of metalloproteinases/antiproteinases of the extracellular matrix in enltured human fibroblasts. Co-incubation of IL-1 and PDGF synergistically increased the expression of stromelysin and interstitial collagenase to 23-fold (for both proteins) over background, while PDGF decreased the IL-1-enhanced expression of FB by 82%. PDGF, but not IL-1, alone or in combination, increased the synthesis of tissue inhibitor of metalloproteinases. RNA Mot analysis indicated that the changes in protein synthesis were regulated at a pretranslational level. Cycloheximide treatment indicated that the effects of PDGF on the metalloproteinases/antiproteinases were not protein-dependent, in contrast to results obtained for FB. The effect of the three dimeric forms of PDGF (AA, AB, and BB) on the synthesis of metalloproteinases and FB was also analyzed. The effects were qualitatively similar for each of the dimeric forms; however, the BB and AB isoforms had considerably greater effects than PDGF-AA. It has been reported that the PDGF receptors found in human fibroblasts have higher binding affinity for the BB and AB isoforms of the growth factor. The results presented in this paper are in accord with the possibility that differences in the biological activity of the three isoforms of PDGF are due to differences in the number or affinity of the binding sites of the target cells, rather than to different activation pathways of the receptor. Thus, PDGF increased cytokine effects on metalloproteinases, while decreasing cytokine effects on complement activator FB. The net effect of these changes may be to decrease inflammation and enhance remodeling early in repair and to enhance matrix stability later in the repair process.

Original languageEnglish
Pages (from-to)12283-12288
Number of pages6
JournalJournal of Biological Chemistry
Volume266
Issue number19
Publication statusPublished - 1991

Fingerprint

Platelet-Derived Growth Factor
Fibroblasts
Interleukin-1
Peptide Hydrolases
Complement Factor B
Metalloproteases
Cytokines
Intercellular Signaling Peptides and Proteins
Protein Isoforms
Repair
Tissue Inhibitor of Metalloproteinases
Platelet-Derived Growth Factor Receptors
Matrix Metalloproteinase 3
Matrix Metalloproteinase 1
Proteins
Cycloheximide
Stiffness matrix
Bioactivity
Extracellular Matrix
Anti-Inflammatory Agents

ASJC Scopus subject areas

  • Biochemistry

Cite this

Differential regulation of the expression of proteinases/ antiproteinases in fibroblasts : Effects of interleukin-1 and platelet-derived growth factor. / Circolo, Antonella; Welgus, Howard G.; Pierce, Glenn F.; Krámer, J.; Strunk, Robert C.

In: Journal of Biological Chemistry, Vol. 266, No. 19, 1991, p. 12283-12288.

Research output: Contribution to journalArticle

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abstract = "We have previously reported that polypeptide growth factors had an anti-inflammatory effect by decreasing the cytokine-enhanced expression of factor B (FB), an activator of the alternative complement pathway, in human fibroblasts. To further characterize the role of cytokines and growth factors in the inflammatory/repair continuum, we have studied the effects of interleukin-1 (IL-1) and platelet-derived growth factor (PDGF) on the expression of metalloproteinases/antiproteinases of the extracellular matrix in enltured human fibroblasts. Co-incubation of IL-1 and PDGF synergistically increased the expression of stromelysin and interstitial collagenase to 23-fold (for both proteins) over background, while PDGF decreased the IL-1-enhanced expression of FB by 82{\%}. PDGF, but not IL-1, alone or in combination, increased the synthesis of tissue inhibitor of metalloproteinases. RNA Mot analysis indicated that the changes in protein synthesis were regulated at a pretranslational level. Cycloheximide treatment indicated that the effects of PDGF on the metalloproteinases/antiproteinases were not protein-dependent, in contrast to results obtained for FB. The effect of the three dimeric forms of PDGF (AA, AB, and BB) on the synthesis of metalloproteinases and FB was also analyzed. The effects were qualitatively similar for each of the dimeric forms; however, the BB and AB isoforms had considerably greater effects than PDGF-AA. It has been reported that the PDGF receptors found in human fibroblasts have higher binding affinity for the BB and AB isoforms of the growth factor. The results presented in this paper are in accord with the possibility that differences in the biological activity of the three isoforms of PDGF are due to differences in the number or affinity of the binding sites of the target cells, rather than to different activation pathways of the receptor. Thus, PDGF increased cytokine effects on metalloproteinases, while decreasing cytokine effects on complement activator FB. The net effect of these changes may be to decrease inflammation and enhance remodeling early in repair and to enhance matrix stability later in the repair process.",
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