MACROPHAGES PRODUCE TGFBI (BIGH3) FOLLOWING INGESTION OF APOPTOTIC CELLS AND REGULATE MMP14 LEVELS AND COLLAGEN TURNOVER IN FIBROBLASTS

• Published in: The Journal of immunology (1950) 2008-04, Vol.180 (7), p.5036-5044
• Main Authors: Nacu, Natalia, Luzina, Irina G., Highsmith, Kendrick, Lockatell, Virginia, Pochetuhen, Kerill, Cooper, Zachary A., Gillmeister, Michael P., Todd, Nevins W., Atamas, Sergei P.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606

Phagocytic clearance of apoptotic cells by macrophages is an essential part in the resolution of inflammation. It coincides with activation of repair mechanisms, including accumulation of extracellular matrix. A possible link between clearance of apoptotic debris and accumulation of extracellular matrix has not been investigated. Production of collagen was measured in primary fibroblasts co-cultured with macrophages. Ingestion of apoptotic cells by monocyte-derived macrophages led to upregulation of collagen. Direct contact between macrophages and fibroblasts was not required for collagen upregulation. Macrophages produced TGF- β following ingestion of apoptotic cells, but the levels of this cytokine were lower than those required for a significant upregulation of collagen. Simultaneously, the levels of TGF-β-induced (TGFBI), or keratoepithelin/BIGH3, mRNA and protein were increased. In contrast, primary alveolar macrophages stimulated collagen production without exposure to apoptotic cells; there was no further increase in the levels of TGFBI, mRNA or protein, or collagen after ingestion of apoptotic cells. Stimulation of fibroblasts with TGFBI downregulated MMP14 levels, decreased DNA binding by p53, increased DNA binding by PU.1, and upregulated collagen protein but not mRNA levels. Overexpression of MMP14 or p53, or siRNA-mediated inhibition of PU.1 led to an increase in MMP14 and a decline in collagen levels, whereas siRNA-mediated inhibition of MMP14 led to elevation of collagen levels. In conclusion, monocyte-derived but not alveolar macrophages produce TGFBI following ingestion of apoptotic cells, leading to downregulation of MMP14 levels in fibroblasts through a mechanism involving p53 and PU.1, and to subsequent accumulation of collagen.