Regulation of growth of human diploid fibrobalasts by factors elaborated by activated lymphoid cells

Abstract

Fibroblasts growth synthesis activities appear to be under exquisite control. This control is mediated in part by substances present in blood plasma or released by other cells. We have studied the role of peripheral blood mononuclear cells (PBM) activated with phytohemagglutinin-P (PHA) on DNA synthesis, proliferation, and the cell cycle of human diploid fibroblasts. Culture medium from activated but not from unactivated PBM cultures inhibited fibroblast DNA synthesis and growth in a dose-dependent manner. The activity, which was designated as lymphocyte factor (LF), was very potent; it inhibited 50% of the DNA synthesis and cell growth at a dilution of 1:160. It has a molecular weight between 50,000 and 100,000 daltons and it is destroyed by trypsin digestion or by heating at 80 degrees C for 30 minutes. The activity was not due to the presence of prostaglandin. Furthermore, using immunoprecipitation and affinity chromatography, it was shown conclusively to to be distinctly different from alpha lymphotoxin (alpha-LT). It was not cytotoxic, as shown by the 51chromium release technique. Using flow microfluorimetry it was shown that the activity regulates fibroblast growth by preventing quiescent cells in the G0 or G1 stage of the cell cycle from entering the S phase. Cells already in S at the time of exposure complete DNA synthesis but cannot divide, and they accumulate in G2. The activity also has marked effects on protein synthesis. Activated mononuclear cells may play a major role in regulating fibroblast growth and synthesis in normally healing wounds and in acute and chronic inflammatory processes.

Nitric oxide-releasing nanoparticles accelerate wound healing in NOD-SCID mice

“…Most notably, they lack CD4 + and CD8 + T lymphocytes, which play a critical role in normal wound healing. Lymphocytes predictably migrate into wounds with a peak at day 7 after wounding, 9 and have been shown to regulate fibroblast replication and collagen synthesis in vitro 7,9,28,29 via stimulatory (TGF-β and lymphotoxin) and inhibitory (interferon-γ) signals. Their role in vivo is less well clarified, as wounds have been shown to heal in the absence of T lymphocytes.…”

Gamma interferon is the lymphokine and beta interferon the monokine responsible for inhibition of fibroblast collagen production and late but not early fibroblast proliferation.

“…This restructuring of tissue with connective tissue results in scar formation, and fibrosis is terminated. Recent studies (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) indicate that mononuclear cells of the immune system may play an important role both in initiating and terminating fibrosis, through the release of LK and MK that stimulate or inhibit fibroblast functions. Of the LK and MK that may terminate fibrosis, those which inhibit fibroblast proliferation and collagen production have been the most extensively studied and characterized (12-15, 17, 18).…”

Collagen synthesis by human fibroblasts. Regulation by transforming growth factor-β in the presence of other inflammatory mediators

“…First, several substances are present at the site of injury and some of them may have opposing effects. For example, platelet-derived growth factor and serum promote fibroblast growth, whereas products of activated mononuclear cells inhibit the growth (Korotzer et al, 1982;Ross et al, 1986). Serum, platelet-derived growth factor and TGF-/i stimulate fibroblasts to synthesize more collagen, whereas y-IFN and mononuclear-cell factors cause inhibition (Narayanan & Page, 1983Rosenbloom et al, 1984;Narayanan et al, 1985;Wrana et al, 1986;Ignotz & Massague, 1986;Ignotz et al, 1987;Czaja et al, 1987).…”