Cytokines modulate the sensitivity of human fibroblasts to stimulation with insulin-like growth factor-I (IGF-I) by altering endogenous IGF-binding protein production

Abstract

Human dermal fibroblasts produce a number of insulin-like growth factor-binding proteins (IGFBPs) including the main circulating form, IGFBP-3. It has been suggested that the regulation of IGFBP secretion may play a major role in modulating insulin-like growth factor (IGF) bioactivity. We have quantified the effects of two cytokines, transforming growth factor-beta 1 (TGF-beta 1) and tumour necrosis factor-alpha (TNF-alpha) which have opposing actions on fibroblast IGFBP-3 production, and examined their subsequent role in IGF-I mitogenesis. TGF-beta 1 caused a dose-dependent increase in IGFBP-3 in serum-free fibroblast-conditioned media. TGF-beta 1 (1 microgram/l) resulted in immunoreactive IGFBP-3 levels reaching 286.5 +/- 22.4% of control after 20 h, the increase being confirmed by Western ligand blot. TNF-alpha caused a dose-dependent decrease in fibroblast IGFBP-3 secretion, 1 microgram TNF-alpha/l reducing IGFBP-3 levels to 32.1 +/- 11.% of control. This effect was not due to cytotoxicity and was not cell-density-dependent. Fibroblast proliferation was examined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric cytochemical bioassay. The addition of IGF-I resulted in dose-dependent growth stimulation after 48 h, the effective range being 20-100 micrograms/l. The IGF-I analogue Long-R3-IGF-I which has little affinity for the IGFBPs was approximately 20-fold more potent in this assay, and was unaffected by exogenous IGFBP-3.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Cytokines on Production of Insulin-like Growth Factor Binding Proteins (IGFBPs) from Human Fibroblasts in Culture

“…Similarly, IGFBP-3 proteins (42/38 KDa species) in the medium were markedly decreased in the culture with IL-1/3 and TNF-a as shown in Western blot. The data for TNF-a are consistent with the report of Yateman et al [3]. There was no change in the ratio of 42 KDa (glycosylated form) to 39 KDa species.…”

“…For example, production of IGFBP-3, which is the major IGFBP in serum, is positively regulated by growth hormone. To our knowledge, the reports regarding the effect of immunoregulatory peptides on production of IGFBPs are limited [3]. We therefore wished to determine whether interleukin (IL)-/3, IL-6, tumor necrosis factor (TNF)-a, or interferon-y affects production of IGFBPs in human fibroblasts.…”

Transforming growth factor-beta induces growth inhibition and IGF-binding protein-3 production in prostatic stromal cells: abnormalities in cells cultured from benign prostatic hyperplasia tissues

“…Transforming growth factor-(TGF-) has been demonstrated in previous studies to be a potent regulator of IGFBP production by various cell types (Martin & Baxter 1991, Martin et al 1992, Yateman et al 1993, Cazals et al 1994, Durham et al 1994, McCusker & Clemmons 1994, Tsukazaki et al 1994, Guo et al 1995, Han et al 1997, Hwa et al 1997. In most cells, TGF-has been shown to be a potent stimulator of IGFBP-3 (Martin & Baxter 1991, Martin et al 1992, Yateman et al 1993, Cazals et al 1994, McCusker & Clemmons 1994, Han et al 1997, Hwa et al 1997).…”

“…In most cells, TGF-has been shown to be a potent stimulator of IGFBP-3 (Martin & Baxter 1991, Martin et al 1992, Yateman et al 1993, Cazals et al 1994, McCusker & Clemmons 1994, Han et al 1997, Hwa et al 1997). TGF-is also known to inhibit the growth of certain cells (Yateman et al 1993, Oh et al 1995.…”

“…In most cells, TGF-has been shown to be a potent stimulator of IGFBP-3 (Martin & Baxter 1991, Martin et al 1992, Yateman et al 1993, Cazals et al 1994, McCusker & Clemmons 1994, Han et al 1997, Hwa et al 1997). TGF-is also known to inhibit the growth of certain cells (Yateman et al 1993, Oh et al 1995. Using a breast cancer model, Oh et al (1995) demonstrated that the stimulation of IGFBP-3 by TGF-2 is critical to TGF--induced growth inhibition, and Rajah et al (1997) showed that IGFBP-3 expression is necessary for TGF-1-induced apoptosis in a prostate cancer model.…”