Monocyte-derived influence on growth of normal human fibroblasts. The contribution of tumour necrosis factor to growth inhibition.

Abstract

The current study demonstrates that whereas high concentrations of recombinant tumour necrosis factor (rTNF, 0.05 microgram/ml) induced enhanced growth of normal human fibroblasts, supernatants from human monocytes with a similar TNF concentration induced cytostasis. This cytostasis was inhibited by an antiserum against rTNF. The TNF activity, measured as cytotoxicity against TNF-sensitive WEHI 164 cells, cochromatographed with the fibroblast growth inhibitory activity upon ion-exchange chromatography of monocyte supernatants. This indicates that TNF contributes to the fibroblast growth inhibition mediated by monocyte supernatants. Alpha interferon (IFN-alpha) abolished the growth of fibroblasts induced by rTNF, whereas rTNF in combination with gamma interferon (IFN-gamma) inhibited growth of fibroblasts. The interferon activity in the supernatants was determined to find out whether the growth-inhibitory activity of natural TNF was due to interferons present in the monocyte supernatants, which might modulate the TNF activity. Cytostasis of fibroblasts was mediated by monocyte supernatants which did not contain IFN-gamma in significant amounts. All supernatants contained IFN-alpha. An antiserum against IFN-alpha partially reduced the cytostasis induced by monocyte supernatants. This cytostasis was totally abolished by rTNF antiserum, suggesting that IFN-alpha modulates the growth-inhibitory activity of TNF in the monocyte supernatants. It appeared that the different effects of recombinant and natural TNF on fibroblast growth can probably not be attributed to monocyte-derived TNF-modulating factors alone. Thus, recombinant and natural TNF may differ in a way that affects their capacity to induce cytostasis of normal fibroblasts.