Downregulation of interleukin 8 gene expression in human fibroblasts: unique mechanism of transcriptional inhibition by interferon.

Abstract

The chemotactic cytokine interleukin 8 (IL-8) is produced upon stimulation by various agents in many cell types, including connective-tissue fibroblasts. Tumor An earlier study described a set of genes activated by TNF in human fibroblasts (8). Some of the genes activated by TNF were also inducible by IFN-,3 or IFN-y. In contrast, IFN-,B or IFN-y inhibited the TNF-induced expression of one of these genes, termed TSG-1. Sequencing of the TSG-1 cDNA revealed that this gene was identical to the gene encoding an important inflammatory cytokine known as IL-8 or NAP-1 (8). IL-8 is a member ofthe family of8-to 10-kDa chemotactic cytokines that includes platelet factor 4, IP-10, Gro, macrophage inflammatory peptides 1 and 2, macrophage chemotactic and activating factor, and several others (reviewed in refs. 15 and 16). In the present study we investigated the inhibitory actions of IFN-13 on TNF-induced IL-8 gene expression in human fibroblasts. Our data indicate that IFN treatment leads to a selective depletion of IL-8 mRNA; this inhibitory effect correlates with a decrease in the rate of IL-8 mRNA transcription. The mechanism responsible for this action appears to be unique in that the inhibitory effect of IFN is established very rapidly and it is not diminished in the presence of inhibitors of protein synthesis, consistent with the idea that this effect is due to a transient modification of a preexisting factor. MATERIALS AND METHODSMaterials. Recombinant human TNF-a (specific activity, 3x 107 units/mg) and IFN-y (5 x 106 units/mg) were from M. Tsujimoto, Suntory Institute for Biomedical Research, Osaka. Escherichia coli-derived recombinant human IFN-f3 (Betaseron, 2 X 108 units/mg) was from Triton Biosciences, Alameda, CA, and recombinant human IFN-p derived from CHO cells (Betaferon, 3 x 108 units/mg) was provided by Wieland Wolf, Bioferon, Laupheim, Germany. The E. coliderived IFN-/3 preparation was used unless specified. Re

The CXC Chemokine GCP-2/CXCL6 Is Predominantly Induced in Mesenchymal Cells by Interleukin-1β and Is Down-Regulated by Interferon-γ: Comparison with Interleukin-8/CXCL8

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AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

“…As early as 1980, IFN had been shown to inhibit endothelial cell motility [58], and later in the 1980s was shown to inhibit tumor-and allogeneic lymphocyte-induced angiogenesis [59] and to selectively damage the tumor microvascular endothelium, leading to coagulation necrosis of murine tumors selected for resistance to IFN's antiproliferative effects [60]. Further investigations of the angiogenesis inhibitory activities of IFN in the 1990s showed that IFNα could downregulate IL-8 production in fibroblasts [61] and bFGF in human tumor cell lines resistant to IFN's antiproliferative effects [62]. Building upon the latter observation in studies of human tumors implanted in nude mice, Fidler and colleagues showed that optimal inhibition of tumor weight, microvessel density, and expression of bFGF, MMP-9 and IL-8 were obtained when low, daily IFN doses were administered, whereas inferior effects were observed when isodense doses were given less often, or when higher IFN doses were used [63][64][65].…”

Differential effects of angiostatin, endostatin and interferon-α1 gene transfer on in vivo growth of human breast cancer cells

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