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Macrophages Produce TGF-β-Induced (β-ig-h3) following Ingestion of Apoptotic Cells and Regulate MMP14 Levels and Collagen Turnover in Fibroblasts¹

Natalia Nacu^*, Irina G. Luzina^*,, Kendrick Highsmith, Virginia Lockatell^*, Kerill Pochetuhen^*, Zachary A. Cooper^*, Michael P. Gillmeister, Nevins W. Todd^*, and Sergei P. Atamas^2,*,

^* University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201

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 cocultured with macrophages. Ingestion of apoptotic cells by monocyte-derived macrophages led to up-regulation of collagen. Direct contact between macrophages and fibroblasts was not required for collagen up-regulation. Macrophages produced TGF-β following ingestion of apoptotic cells, but the levels of this cytokine were lower than those required for a significant up-regulation 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 down-regulated MMP14 levels, decreased DNA binding by p53, increased DNA binding by PU.1, and up-regulated collagen protein but not mRNA levels. Overexpression of MMP14 or p53, or small interfering RNA-mediated inhibition of PU.1 led to an increase in MMP14 and a decline in collagen levels, whereas small interfering RNA-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 the down-regulation of MMP14 levels in fibroblasts through a mechanism involving p53 and PU.1, and to subsequent accumulation of collagen.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a National Institutes of Health Grant 1 R01 HL074067 (to S.P.A.), a Veterans Administration Merit Review grant (to S.P.A.), and Maryland Chapter of Arthritis Foundation Research Awards (to I.G.L. and S.P.A.).

² Address correspondence and reprint requests to Dr. Sergei P. Atamas, University of Maryland School of Medicine, 10 South Pine Street, MSTF 8-34, Baltimore, MD 21201. E-mail address: satamas{at}umaryland.edu

³ Abbreviations used in this paper: TGFBI, TGF-β induced; BIGH3, β-ig-h3; MDM, monocyte-derived macrophage; AM, alveolar macrophage; TDM, THP-1-derived macrophage; siRNA, small interfering RNA; CAT, chloramphenicol acetyltransferase; rh, recombinant human.