Fibroblast growth enhancing activity of tumor necrosis factor and its relationship to other polypeptide growth factors.

Abstract

Tumor necrosis factor (TNF) is a monocyte-derived protein cytotoxic or cytostatic for some tumor cell lines. Here we show that highly purified E. coli-derived recombinant human TNF stimulated the growth of human FS-4 diploid fibroblasts. Stimulation of cell growth was demonstrable at a TNF concentration of 10 pg/ml (3 X 10(-13) M). Maximal stimulation was attained at TNF concentrations of 10 ng/ml (3 X 10(-10) M) or higher. Growth-stimulatory activity of TNF was inhibited by an mAb neutralizing the cytotoxic activity of TNF. Growth stimulation was not inhibited by another mAb specific for TNF, lacking neutralizing activity for the cytotoxic activity of TNF. Growth stimulation by TNF was more marked and more sustained in the presence of greater than or equal to 10% FCS than in medium with less than or equal to 5% FCS. Addition of TNF to confluent FS-4 cultures also produced a marked stimulation of cell growth in the presence of fresh FCS, while a much less marked stimulation was seen in the absence of FCS. Stimulation of confluent cultures by TNF in serum-free medium was enhanced by insulin, suggesting that insulin or insulin-like growth factor(s) in the serum can act synergistically with TNF in producing growth stimulation. While the growth-stimulatory effects of TNF and insulin were synergistic, the actions of TNF and epidermal growth factor (EGF) were less than additive, suggesting that TNF and EGF may activate identical or similar pathways. We conclude that stimulation of cell growth is probably a physiological function of TNF, and that the cytotoxic and cytostatic actions of TNF may be the result of an anomalous growth signal transduction in neoplastic cells lacking the constraints of normal growth control mechanisms.

Therapeutic Interventions in Oral Submucous Fibrosis: An Experimental and Clinical Study

“…Both interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF-a) stimulate fibroblast proliferation in vitro [27,33], and intradermal injections of TNF-a stimulate the accumulation of fibroblasts and collagen [23]. Similarly, IL-6 has been implicated in the development of fibrosis [16].…”

Enhanced Production Of Interleukin‐1 And Tumor Necrosis Factor α By Cultured Peripheral Blood Monocytes From Patients With Scleroderma

“…Since both IL-1 and T N F a are known to stimulate the proliferation of fibroblasts (2,5), the enhanced production of these molecules might participate in the pathogenesis of sclerosis via fibroblast stimulation. There have been several studies of IL-1 production by monocytes from patients with SSc.…”

“…Tumor necrosis factor a (TNFa), a product of activated macrophages, has been shown to possess multiple inflammatory and immunoregulatory properties (3,4), including the ability to stimulate fibroblast growth (5). Studies of IL-1 and TNFa production in SSc patients are important because of the stimulatory activity of IL-I and TNFa on fibroblasts.…”

Tumor necrosis factor/cachectin stimulates peritoneal macrophages, polymorphonuclear neutrophils, and vascular endothelial cells to synthesize and release platelet-activating factor.

“…However, several lines of evidence indicate that this is not the only biologic activity of TNF. This factor can stimulate fibroblast proliferation (48,49), is pyrogenic (50), affects lipid metabolism (51), and modulates several functions of endothelial cells (52,53) . Furthermore, recent reports indicate that TNF is a mediator of inflammatory reactions.…”