Cross-talk between MCP-3 and TGFbeta promotes fibroblast collagen biosynthesis.

Abstract

Recent studies have demonstrated upregulation of monocyte chemoattractant protein-3 (MCP-3/CCL7) in fibrosis and have suggested that in addition to a major role in regulating leucocyte recruitment this chemokine may also promote extracellular matrix (ECM) overproduction by fibroblasts. In the present study we explore interplay between MCP-3 and transforming growth factor beta (TGFbeta), a potent profibrotic cytokine. We demonstrate that MCP-3 promotes activation of TGFbeta signalling pathways leading to increased type I collagen secretion. In addition we show that MCP-3 gene expression is stimulated by recombinant TGFbeta1, raising the possibility for synergy between these two mediators in the fibrotic microenvironment. Comparison of downstream signalling pathways that regulate collagen gene activation by both cytokines confirms the central role of MAPK pathway activation in mediating the effects of both factors. An additive effect of these two agonists was demonstrated by comparative microarray analysis for key TGFbeta regulated transcripts including PAI-1, OSF2 and IGFBP6. Together, our results confirm cross-talk between MCP-3 and TGFbeta that may be critical in the development of fibrosis.

• Authors: Voon H Ong, Maria Teresa Carulli, Shiwen Xu, Korsa Khan, Gisela Lindahl, David J Abraham, Christopher P Denton
• Journal: Experimental cell research (Exp Cell Res) Vol. 315 Issue 2 Pg. 151-61 (Jan 15 2009) ISSN: 1090-2422 [Electronic] United States
• PMID: 19038247 (Publication Type: Journal Article)

Chemical References

• Chemokine CCL7
• Collagen Type I
• Enzyme Inhibitors
• Phosphoinositide-3 Kinase Inhibitors
• Pteridines
• RNA, Small Interfering
• Recombinant Proteins
• SD-208
• Smad3 Protein
• Smad3 protein, mouse
• Transforming Growth Factor beta
• Collagen
• Proto-Oncogene Proteins c-akt
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Cells, Cultured
• Chemokine CCL7 (genetics, metabolism, pharmacology)
• Collagen (biosynthesis, genetics)
• Collagen Type I (biosynthesis, genetics)
• Enzyme Inhibitors (pharmacology)
• Fibroblasts (cytology, drug effects, metabolism)
• Gene Expression (drug effects)
• Mice
• Oligonucleotide Array Sequence Analysis
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pteridines (pharmacology)
• RNA, Small Interfering (genetics)
• Recombinant Proteins (pharmacology)
• Signal Transduction (drug effects, physiology)
• Smad3 Protein (genetics, metabolism)
• Transforming Growth Factor beta (genetics, metabolism, pharmacology)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)