Cross-talk between MCP-3 and TGFbeta promotes fibroblast collagen biosynthesis.
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.
Ong
Voon H
VH
Centre for Rheumatology and Connective Tissue Diseases, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK.
Carulli
Maria Teresa
MT
Xu
Shiwen
S
Khan
Korsa
K
Lindahl
Gisela
G
Abraham
David J
DJ
Denton
Christopher P
CP
D000818:Animals; D002478:Cells, Cultured; D054410:Chemokine CCL7 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D054410:Chemokine CCL7; D003094:Collagen; D024042:Collagen Type I; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011621:Pteridines; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; C511004:SD-208; C497791:Smad3 protein, mouse