title: Monomeric C-reactive protein inhibits renal cell-directed complement activation mediated by properdin.
abstract: Previous studies have shown that complement activation on renal tubular cells is involved in the induction of interstitial fibrosis and cellular injury. Evidence suggests that the tubular cell damage is initiated by the alternative pathway (AP) of complement with properdin having an instrumental role. Properdin is a positive regulator of the AP, which can bind necrotic cells as well as viable proximal tubular epithelial cells (PTECs), inducing complement activation. Various studies have indicated that in the circulation there is an unidentified inhibitor of properdin. We investigated the ability of C-reactive protein (CRP), both in its monomeric (mCRP) and pentameric (pCRP) form, to inhibit AP activation and injury in vitro on renal tubular cells by fluorescent microscopy, ELISA, and flow cytometry. We demonstrated that preincubation of properdin with normal human serum inhibits properdin binding to viable PTECs. We identified mCRP as a factor able to bind to properdin in solution, thereby inhibiting its binding to PTECs. In contrast, pCRP exhibited no such binding and inhibitory effect. Furthermore, mCRP was able to inhibit properdin-directed C3 and C5b-9 deposition on viable PTECs. The inhibitory ability of mCRP was not unique for viable cells but also demonstrated for binding to necrotic Jurkat cells, a target for properdin binding and complement activation. In summary, mCRP is an inhibitor of properdin in both binding to necrotic cells and viable renal cells, regulating complement activation on the cell surface. We propose that mCRP limits amplification of tissue injury by controlling properdin-directed complement activation by damaged tissue and cells.
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; and J.O_flynn@lumc.nl.
authors.forename: Joseph
authors.initials: J
authors.lastname: O'Flynn
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; and.
authors.forename: Pieter
authors.initials: P
authors.lastname: van der Pol
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; and.
authors.forename: Karen O
authors.initials: KO
authors.lastname: Dixon
authors.affiliation: Third Department of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Prohászka
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; and.
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; and.
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
mesh_terms: D002097:C-Reactive Protein / Q000378:metabolism*; D002460:Cell Line; D003167:Complement Activation / Q000187:drug effects*; D003176:Complement C3 / Q000378:metabolism*; D003182:Complement C5 / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D011414:Properdin / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects
chemical_list: D003176:Complement C3; D003182:Complement C5; D011414:Properdin; D002097:C-Reactive Protein
keywords: C-reactive protein; alternative pathway; kidney; properdin; proximal tubular epithelial cell