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Macrophage‐dependent TGFBI‐mediated regulation of collagen levels following ingestion of apoptotic cells
Author(s) -
Nacu Natalia,
Luzina Irina G,
Todd Nevins W,
Atamas Sergei P
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1072.8
Subject(s) - downregulation and upregulation , fibroblast , extracellular matrix , apoptosis , chemistry , microbiology and biotechnology , macrophage , monocyte , tgfbi , immunology , biology , in vitro , biochemistry , gene
Inflammation resolution involves phagocytic clearance of apoptotic cells coinciding with activation of repair that includes accumulation of extracellular matrix. The regulation of collagen levels by macrophages during this process has not been studied. Collagen levels were increased in co‐cultures of primary fibroblasts with monocyte‐derived but not with alveolar macrophages following ingestion of apoptotic cells; direct contact between macrophages and fibroblasts was not required for collagen upregulation. Macrophages produced TGF‐β at the levels that were lower than those required for a significant upregulation of collagen, but the levels of TGF‐β‐induced (TGFBI), mRNA and protein were increased in monocyte‐derived but not alveolar macrophages following ingestion of apoptotic cells. Fibroblast activation with recombinant TGFBI led to decreased DNA binding by p53, increased DNA binding by PU.1, downregulation of matrix metalloproteinase 14 (MMP14) levels, and upregulation of collagen protein but not mRNA levels. Overexpression of p53 or MMP14, or siRNA‐mediated inhibition of PU.1 increased MMP14 and decreased collagen levels. In conclusion, following ingestion of apoptotic cells, monocyte‐derived but not alveolar macrophages produce TGFBI that employs p53 and PU.1 to downregulate MMP14, leading to a subsequent collagen accumulation. Support: NIH NHLBI 1R01HL074067 and VA Merit (SPA).