title: The α7β0 isoform of the complement regulator C4b-binding protein induces a semimature, anti-inflammatory state in dendritic cells.
abstract: The classical pathway complement regulator C4b-binding protein (C4BP) is composed of two polypeptides (α- and β-chains), which form three plasma oligomers with different subunit compositions (α7β1, α7β0, and α6β1). We show in this article that the C4BP α7β0 isoform (hereafter called C4BP[β(-)] [C4BP lacking the β-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 β-chain (α7β1 and α6β1; C4BP[β(+)]) neither interfered with the normal maturation of DCs nor competed with C4BP(β(-)) activity on these cells. Immature DCs (iDCs) treated with C4BP(β(-)) 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(β(-)) prevented the induction of IDO and BIC-1, whereas TGF-β1 expression was maintained to the level of iDCs. C4BP(β(-))-treated DCs were also unable to release proinflammatory Th1 cytokines (IL-12, TNF-α, IFN-γ, 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(β(-))-treated DCs failed to enhance allogeneic T cell proliferation, impairing IFN-γ 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 α-chain is necessary for the tolerogenic activity of C4BP(β(-)). Our data demonstrate a novel anti-inflammatory and immunomodulatory function of the complement regulator C4BP, suggesting a relevant role of the acute-phase C4BP(β(-)) isoform in a number of pathophysiological conditions and potential applications in autoimmunity and transplantation.
authors: Human Molecular Genetics Group, Bellvitge Biomedical Research Institute, 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
authors: Rut
authors: R
authors: Olivar
authors: Ana
authors: A
authors: Luque
authors: Mar
authors: M
authors: Naranjo-Gómez
authors: Josep
authors: J
authors: Quer
authors: Pablo
authors: P
authors: García de Frutos
authors: Francesc E
authors: FE
authors: Borràs
authors: Santiago
authors: S
authors: Rodríguez de Córdoba
authors: Anna M
authors: AM
authors: Blom
authors: Josep M
authors: JM
authors: Aran
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D050716:Complement C4b-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D003713:Dendritic Cells / Q000737:chemistry* / Q000276:immunology* / Q000473:pathology; D057809:HEK293 Cells; D006649:Histocompatibility Antigens / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000502:physiology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C055609:C4BPA protein, human; D050716:Complement C4b-Binding Protein; D006649:Histocompatibility Antigens; D020033:Protein Isoforms