7684044

pubmed:Citation

3

Macrophage expression of urokinase-type plasminogen activator (uPA) appears to play a role in their release of matrix-bound basic fibroblast growth factor (bFGF) and transforming growth factor-beta (TGF-beta). In experiments reported here, we have examined the potential regulatory effects of bFGF and TGF-beta 1 on macrophage uPA expression. TGF-beta 1 stimulated in a dose- and time-dependent manner the expression of secreted membrane and intracellular uPA activities by a macrophage cell line (RAW264.7). When examined at similar concentrations, bFGF had little effect, and interleukin-1 alpha, tumor necrosis factor-alpha, and monocyte colony stimulating factor had no effect on macrophage uPA expression. Exposure of macrophages to TGF-beta 1 led to a rapid and sustained increase in the steady-state levels of uPA mRNA that was independent of de novo protein synthesis and was completely inhibited by actinomycin D. However, the TGF-beta 1-induced increase in uPA mRNA was largely unaffected by subsequent incubation of cells with actinomycin D. The protein kinase C inhibitor H7 markedly reduced the ability of TGF-beta 1 to stimulate expression of uPA activity. Likewise, okadaic acid and microcystin, inhibitors of serine/threonine phosphatases, potentiated the ability of TGF-beta 1 to upregulate macrophage uPA expression. TGF-beta 1 primed cells converted nearly all added plasminogen to plasmin and expressed sixfold more membrane-bound plasmin than control cells. Preincubation of TGF-beta 1 with either serum or methylamine-modified alpha 2-macroglobulin did not affect its ability to induce macrophage uPA expression. When control and TGF-beta 1-primed macrophages were cultured on matrices containing bound 125I-bFGF, their release of 125I-bFGF was increased five and tenfold, respectively, in the presence of plasminogen. The ability of TGF-beta to induce macrophage uPA expression and the plasmin-dependent release of matrix-bound bFGF may provide an indirect mechanism by which TGF-beta stimulates angiogenesis.

eng

IM

MEDLINE

0021-9541

Print

NLM

595-605

pubmed-meshheading:7684044-1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, pubmed-meshheading:7684044-Animals, pubmed-meshheading:7684044-Cell Line, pubmed-meshheading:7684044-Dactinomycin, pubmed-meshheading:7684044-Drug Synergism, pubmed-meshheading:7684044-Ethers, Cyclic, pubmed-meshheading:7684044-Extracellular Matrix, pubmed-meshheading:7684044-Fibroblast Growth Factor 2, pubmed-meshheading:7684044-Gene Expression, pubmed-meshheading:7684044-Humans, pubmed-meshheading:7684044-Isoquinolines, pubmed-meshheading:7684044-Macrophages, pubmed-meshheading:7684044-Methylamines, pubmed-meshheading:7684044-Mice, pubmed-meshheading:7684044-Microcystins, pubmed-meshheading:7684044-Okadaic Acid, pubmed-meshheading:7684044-Peptides, Cyclic, pubmed-meshheading:7684044-Piperazines, pubmed-meshheading:7684044-Plasminogen Activator Inhibitor 1, pubmed-meshheading:7684044-Protein Kinase C, pubmed-meshheading:7684044-RNA, Messenger, pubmed-meshheading:7684044-Transforming Growth Factor beta, pubmed-meshheading:7684044-Urokinase-Type Plasminogen Activator, pubmed-meshheading:7684044-alpha-Macroglobulins

Transforming growth factor-beta 1 stimulates macrophage urokinase expression and release of matrix-bound basic fibroblast growth factor.

Journal Article, Research Support, U.S. Gov't, P.H.S.