"The processes in atherogenesis are complex and are controlled by both stimulatory and inhibitory influences . Although macrophages secrete mitogens such as platelet-derived growth factor (PDGF) ; fibroblast growth factor (FGF) ; interleukin-1 (IL-1) , transforming growth factor a  and a heparin-binding epidermal growth factor-like molecule , there are also a number of macrophage products which have inhibitory effects on SMC growth. Transforming growth factor b (TGFb) has been reported to cause stimulation or inhibition depending on cell culture conditions   and on the concentration of TGFb . "
[Show abstract][Hide abstract] ABSTRACT: Monocyte/macrophages produce a variety of substances which may influence the function of smooth muscle cells (SMC). During atherogenesis, macrophages are thought to modulate SMC migration, proliferation and synthesis of extracellular matrix. Such modulation is the balance between stimulatory and inhibitory influences. Thus, for example, our earlier studies have shown that macrophages not only secrete mitogens, but also produce small molecular weight inhibitors of SMC proliferation. In the present study, we have used a co-culture system in which human monocyte/macrophages were separated from human arterial SMC (hSMC) by a filter with the optional addition of a 12 kDa cut-off dialysis membrane, in order to assess their effect on hSMC growth. We have found that human peripheral blood-derived monocytes produced a substance of < 12 kDa that inhibited hSMC growth in the co-culture system. The monocyte-derived factor causing this effect was completely blocked by indomethacin, indicating that growth-inhibitory factors produced by the monocytes were cyclooxygenase products. We have shown that PGE1 and PGE2 inhibit hSMC growth, making them likely candidates for the effector molecules released from monocytes in our co-culture system.
"Matrix turnover is a composite of secretion and degradation and macrophages may play a role in regulating both processes. On the secretion side, macrophages can produce factors such as TGFi, PDGF and IL-1   which increase collagen synthesis in VSMC,  and factors such as TNFh which is known to reduce collagen synthesis in fibroblasts  . With regard to degradation, this is largely determined by the action of matrix metalloproteinases (MMPs) which are produced by both macrophages and VSMC     . "
[Show abstract][Hide abstract] ABSTRACT: Extracellular matrix remodelling occurs during atherosclerosis dictating the structure of the plaque and thus the resistance to rupture. Monocytes and macrophages are believed to play a role in this remodelling. In the present study, filter-separated co-culture has been used to study the effect of monocytes on procollagen turnover by human vascular smooth muscle cells (VSMC). In this system, freshly isolated human peripheral blood monocytes inhibited procollagen secretion from VSMC without affecting either degradation of procollagen, or DNA synthesis by the VSMC. Insertion of a 12 kDa dialysis membrane between the two cell types and treatment with indomethacin showed that the inhibitory factor was of low molecular weight and was cyclooxygenase-dependent. Pre-incubation of each cell type with indomethacin demonstrated that monocyte, but not VSMC cyclooxygenase was required. Thus, the inhibitory effect on procollagen secretion was due, most likely, to monocyte prostaglandins. Neither inhibition of thromboxane synthetase, nor blocking IL-1 activity, reduced the inhibitory activity. Addition of prostaglandins PGE1, PGE2 and PGF2alpha to VSMC cultures caused a reduction in procollagen secretion which was equivalent to, but was not additive with, the maximal effect achieved by monocytes. Monocytes and macrophages are a major source of prostaglandins and these molecules are likely to play an important role in collagen turnover within lesions.
"Macrophage-derived mitogenic activity has been demonstrated to be released by macrophages from a variety of sources including mouse peritoneal macrophages (Martin et al., 1981), alveolar macrophages (Bittermann et al., 1982), macrophage cell lines (Wharton et al., 1982) and stimulated monocytes (DeLustro et al., 1980; Glenn and Ross, 1981; Parrott et al., 1982; Leslie et al., 1984). Macrophages are known to synthesise growth stimulatory factors such as platelet-derived growth factor (PDGF) (Shimokado et al., 1985); fibroblast growth factor (FGF) (Baird et al ., 1985); and interleukin-1 (IL-1) (Metcalf, 1989). "
[Show abstract][Hide abstract] ABSTRACT: P388D1 macrophage-like cells have previously been shown to produce both mitogenic and inhibitory regulators of porcine smooth muscle cell (pSMC) growth. The mitogenic activity was shown to have a molecular mass of > 10 kDa while the inhibitory activity was in the range of 2-6 kDa. In the present study, we present a novel dialysis culture system where P388D1 cells were grown in dialysis membranes with a 12 kDa cut-off which allowed continuous production of fractions of the culture medium. Using pSMC as target cells, mitogenic activity was found to be retained by the dialysis membrane while the low molecular mass inhibitory activity passed freely through the membrane. The effect of the macrophage-activators phorbol myristate acetate (PMA), concanavalin A (ConA) and interferon-gamma in combination with lipopolysaccharide (IFN gamma/LPS) were investigated in the dialysis culture system. PMA, ConA and IFN gamma/LPS were found to enhance the production of mitogenic activity by P388D1 cells. PMA also increased the production of growth-inhibitory activity, while ConA abolished inhibitor production and IFN gamma/LPS had no effect on the amount of inhibitory activity produced by P388D1 cells. The experiments show that the balance of production of mitogenic and inhibitory activities by macrophages can be modulated by agents that alter the state of activation of the cells. This could be of profound significance in the influence of macrophages on smooth muscle cell growth during the development of atherosclerosis.
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