The Journal of Experimental Medicine
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Published 20 June 2005. doi:10.1084/jem.20050189
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 12, 1937-1948
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ARTICLE

 C4b-binding protein binds to necrotic cells and DNA, limiting DNA release and inhibiting complement activation

Leendert A. Trouw1, Sara C. Nilsson1, Isabel Gonçalves2, Göran Landberg1, and Anna M. Blom1

1 Department of Laboratory Medicine, University Hospital Malmö, Lund University, S-205 02 Malmö, Sweden
2 Department of Clinical Sciences, University Hospital Malmö, Lund University, S-205 02 Malmö, Sweden

CORRESPONDENCE Anna M. Blom: Anna.Blom{at}med.lu.se

After cell death, via apoptosis or necrosis, the uptake of dead cells by neighboring cells or phagocytes prevents the release of intracellular content. An array of molecules, including initiation molecules of the complement system, are involved in marking dead cells for uptake. After binding of these molecules, complement activation takes place, which when uncontrolled might result in a proinflammatory state. In the current study we demonstrate that complement inhibitor, C4b-binding protein (C4BP), binds strongly to necrotic cells, irrespective of the cell type used or the method of induction. After binding of the C4BP–protein S (PS) complex to necrotic cells via PS-phosphatidylserine and C4BP-DNA interactions, C4BP-PS inhibits complement activation on these cells. C4BP binds DNA via a patch of positively charged amino acids, mainly on the second complement control domain of the C4BP {alpha}-chain (affinity constant: 190 nM). Furthermore, C4BP limits DNA release from necrotic cells and inhibits DNA-mediated complement activation in solution. The C4BP–necrotic cell interaction also occurs in vivo as necrotic areas of arteriosclerotic plaques and of various cancers stain strongly positive for C4BP. This study describes a novel mechanism in which C4BP limits the inflammatory potential of necrotic cells.

Abbreviations used: C4BP, C4b-binding protein; C4BP-PS, C4b-binding protein–protein S complex; CCP, complement control protein (domain); dsDNA, double-stranded DNA; dNTP, deoxyribonucleoside triphosphate; MBL, mannose-binding lectin; NHS, normal human serum; PS, protein S; SAP, serum amyloid–P component; ssDNA, single-stranded DNA.


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