Regulation of proteolytic activity in human bone marrow stromal cells by basic fibroblast growth factor, interleukin-1, and transforming growth factor beta

Abstract

Plasminogen activators (PAs) and/or plasmin may be involved in hematopoietic regulation. These enzymes release biologically relevant cytokines such as basic fibroblast growth factor (bFGF) from matrix and cell surfaces. In addition, transforming growth factor beta (TGF beta) and interleukin-1 beta (IL-1 beta) are converted from inactive to active forms by plasmin. Therefore, we studied the regulation of PAs and their specific inhibitors, PA inhibitor 1 (PAI-1) and PA inhibitor 2 (PAI-2), in human bone marrow stromal fibroblasts by IL-1 beta, bFGF, and TGF beta. All three cytokines stimulated PA secretion. IL-1 beta at 10(4) U/mL increased urokinase (u-PA) levels approximately 10-fold, bFGF at 0.2 ng/mL also increased production 10-fold, but increased predominantly tissue PA (t-PA) expression. TGF beta at 0.2 ng/mL increased u-PA production up to 300-fold. PAI-1 and PAI-2 are also regulated by these cytokines. IL-1 beta decreased PAI-1 levels by 50% and stimulated PAI-2 levels sixfold. bFGF had minimal effects on PAI-1 and TGF beta increased PAI-1 levels twofold. Neither of these agents had an effect on PAI-2 levels. Thus, three cytokines relevant to bone marrow physiology regulate PA and inhibitor production by human bone marrow stromal fibroblasts. In this manner PA and plasmin generation in specific microenvironments in the bone marrow may be one of the factors orchestrating the complex series of events, which results in an efficient exquisitely regulated hematopoietic process.

Inflammation Location, But Not Type, Determines the Increase in TGF-β1 and IGF-1 Expression and Collagen Deposition in IBD Intestine

“…In femptomolar concentrations (10)(11)(12)(13)(14)(15) it is chemotactic for fibroblasts (23). At higher concentrations, TGF-␤1 stimulates fibroblasts to increase collagen production (9), while decreasing collagen degradation by suppressing MMP-1 secretion, and increasing TIMP-1 (25) and plasminogen activator inhibitors (PAIs) activity (33,34). The net result of these multiple actions is the accumulation of collagen within the tissue.…”

Expression of urokinase plasminogen activator and the urokinase plasminogen activator receptor in myeloma cells

“…Furthermore, our results suggest that the expression of uPAR is dependent on the stage of myeloma cell maturation, with immature cells having the highest expression. uPA can be produced by a number of cell types in the BM environment, making it possible for myeloma cells to bind either endogenously or exogenously derived uPA (Hoekman et al, 1991;Hannocks et al, 1992). The consecutive activation of plasminogen to plasmin will focus proteolytic activity on the surface of the myeloma cells.…”

Urokinase-type-plasminogen-activator(UPA) production by human breast (myo)fibroblastsin vitro: Influence of transforming growth factor-β1 (TGFβ1) compared with factor(s) released by human epithelial-carcinoma cells

“…TGF␤ 1 has been shown to play a crucial role in the formation and maintenance of the extracellular matrix through mechanisms including modulation of the plasminogen activator system. This has been demonstrated in vitro not only for cultured human epithelial cell lines (Keski-Oja et al, 1988;Arnoletti et al, 1995), but also for cultured human fibroblasts (Lund et al, 1987;Keski-Oja et al, 1988;Hamilton et al, 1991;Hannocks et al, 1992;Cullen et al, 1997).…”

“…PAI-1 not only inhibits the enzymatic activity of uPA, it can also influence cell migration and prevent cell adhesion (reviewed by Andreasen et al, 1997). In contrast, it has been reported that in human lung-cancer cells (Keski-Oja et al, 1988), and breast-cancer cells (Arnoletti et al, 1995), as well as in human synovial fibroblasts (Hamilton et al, 1991), and bone-marrow fibroblasts (Hannocks et al, 1992), TGF␤ 1 actually increased uPA expression. These differing influences of TGF␤ 1 on PA expression by human cancer cells and fibroblasts of different tissue origin, together with our observations in one of the tumor-derived fibroblast strains (T3), indicate that TGF␤ 1 is not a down-regulator of plasminogenactivator activity in general, and that caution is warranted.…”