The alpha(7)beta(0) Isoform of the Complement Regulator C4b-Binding Protein Induces a Semimature, Anti-Inflammatory State in Dendritic Cells

Research output: Contribution to journalArticle

Abstract

The classical pathway complement regulator C4b-binding protein (C4BP) is composed of two polypeptides (alpha- and beta-chains), which form three plasma oligomers with different subunit compositions (alpha(7)beta(1), alpha(7)beta(0), and alpha(6)beta(1)). We show in this article that the C4BP alpha(7)beta(0) isoform (hereafter called C4BP[beta(-)] [C4BP lacking the beta-chain]), overexpressed under acute-phase conditions, induces a semimature, tolerogenic state on human monocyte-derived dendritic cells (DCs) activated by a proinflammatory stimulus. C4BP isoforms containing beta-chain (alpha(7)beta(1) and alpha(6)beta(1); C4BP[beta(+)]) neither interfered with the normal maturation of DCs nor competed with C4BP(beta(-)) activity on these cells. Immature DCs (iDCs) treated with C4BP(beta(-)) retained high endocytic activity, but, upon LPS treatment, they did not upregulate surface expression of CD83, CD80, and CD86. Transcriptional profiling of these semimature DCs revealed that treatment with C4BP(beta(-)) prevented the induction of IDO and BIC-1, whereas TGF-beta 1 expression was maintained to the level of iDCs. C4BP(beta(-))-treated DCs were also unable to release proinflammatory Th1 cytokines (IL-12, TNF-alpha, IFN-gamma, IL-6, IL-8) and, conversely, increased IL-10 secretion. They prevented surface CCR7 overexpression and, accordingly, displayed reduced chemotaxis, being morphologically indistinguishable from iDCs. Moreover, C4BP(beta(-))-treated DCs failed to enhance allogeneic T cell proliferation, impairing IFN-gamma production in these cells and, conversely, promoting CD4(+)CD127(low/neg) CD25(high)Foxp3(+) T cells. Deletion mutant analysis revealed that the complement control protein-6 domain of the alpha-chain is necessary for the tolerogenic activity of C4BP(beta(-)). Our data demonstrate a novel anti-inflammatory and immunomodulatory function of the complement regulator C4BP, suggesting a relevant role of the acute-phase C4BP(beta(-)) isoform in a number of pathophysiological conditions and potential applications in autoimmunity and transplantation. The Journal of Immunology, 2013, 190: 2857-2872.

Details

Authors
  • Rut Olivar
  • Ana Luque
  • Mar Naranjo-Gomez
  • Josep Quer
  • Pablo Garcia de Frutos
  • Francesc E. Borras
  • Santiago Rodriguez de Cordoba
  • Anna Blom
  • Josep M. Aran
Organisations
External organisations
  • L'Hospitalet de Llobregat, Barcelona
  • Autonomous University of Barcelona
  • Institutd' Investigacions Biomèdiques August Pi iSunyer (IDIBAPS)
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area
Original languageEnglish
Pages (from-to)2857-2872
JournalJournal of Immunology
Volume190
Issue number6
Publication statusPublished - 2013
Publication categoryResearch
Peer-reviewedYes