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Synthesis of C-X-C and C-C Chemokines by Human Peritoneal Fibroblasts - Induction by Macrophage-Derived Cytokines

Item Type:Article
Title:Synthesis of C-X-C and C-C Chemokines by Human Peritoneal Fibroblasts - Induction by Macrophage-Derived Cytokines
Creators Name:Witowski, J. and Thiel, A. and Dechend, R. and Dunkel, K. and Fouquet, N. and Bender, T.O. and Langrehr, J.M. and Gahl, G.M. and Frei, U. and Joerres, A.
Abstract:Leukocyte accumulation during peritonitis is believed to be controlled by chemotactic factors released by resident peritoneal macrophages or mesothelial cells. Recent data indicate, however, that in many tissues fibroblasts play a key role in mediating leukocyte recruitment. We have therefore examined human peritoneal fibroblasts (HPFBs) for the expression and regulation of C-X-C and C-C chemokines. Quiescent HPFBs secreted monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8 constitutively. This release could be dose-dependently augmented with the pro-inflammatory cytokines IL-1beta and tumor necrosis factor-alpha. Stimulated IL-8 production reached a plateau within 48 hours while MCP-1 continued to accumulate throughout 96 hours. Induction of IL-8 and MCP-1 synthesis by HPFBs was also triggered by peritoneal macrophage-conditioned medium. This effect was partly related to the presence of IL-1beta as demonstrated by IL-1 receptor antagonist inhibition. Pretreatment of HPFBs with actinomycin D or puromycin dose-dependently reduced cytokine-stimulated IL-8 and MCP-1 secretion, which suggested de novo chemokine synthesis. Indeed, exposure of HPFBs to IL-1beta and tumor necrosis factor-alpha produced a significant up-regulation of IL-8 and MCP-1 mRNA. This effect was associated with the rapid induction of nuclear factor-kappaB binding activity mediated through p65 and p50 subunits, and with a transient increase in the mRNA expression for RelB and inhibitory protein kappaB-alpha proteins. These data indicate that peritoneal fibroblasts are capable of generating large quantities of chemokines under a tight control of nuclear factor-kappaB/Rel transcription factors. Thus, peritoneal fibroblast-derived chemokines may contribute to the intraperitoneal recruitment of leukocytes during peritonitis.
Keywords:Cultured Cells, Chemokine CCL2, CC Chemokines, CXC Chemokines, Conditioned Culture Media, Cytokines, Fibroblasts, Gene Expression, I-kappa B Proteins, Interleukin-8, Macrophages, NF-kappa B, Peritoneum, Polymerase Chain Reaction, Protein Biosynthesis, Proto-Oncogene Proteins, Recombinant Proteins, Transcription Factor RelB, Genetic Transcription
Source:American Journal of Pathology
Publisher:American Society for Investigative Pathology
Page Range:1441-1450
Date:April 2001
Official Publication:http://ajp.amjpathol.org/cgi/content/abstract/158/4/1441
PubMed:View item in PubMed

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