C4b Binding Protein Binds to CD154 Preventing CD40 Mediated Cholangiocyte Apoptosis: A Novel Link between Complement and Epithelial Cell Survival

Williams, Kevin T.; Young, Steven P.; Negus, Alison; Young, Lawrence S.; Adams, David H.; Afford, Simon C.

doi:10.1371/journal.pone.0000159

Cited by 20 publications

(18 citation statements)

References 36 publications

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“…CVF significantly affected the disease score and incidence only at day 26 at the concentrations and intervals used. C4BP may interact with CD4034 and CD40L35 and could affect antibody production. However, this possibility was excluded as the levels of antibodies against CII were the same in all the experimental groups (fig 4D).…”

Section: Resultsmentioning

confidence: 99%

C4b-binding protein (C4BP) inhibits development of experimental arthritis in mice

2008

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Objectives:To assess the human complement inhibitor C4b-binding protein (C4BP) for treatment of arthritis.Methods:We have used two mouse models of rheumatoid arthritis (RA) to assess the therapeutic effect of C4BP on different phases of arthritis, the collagen antibody-induced arthritis (CAIA), an acute antibody-induced disease and the collagen-induced arthritis (CIA), which carries the full complexity of arthritis.Results:Purified human C4BP injected intraperitoneally alleviated CAIA significantly in a manner similar to cobra venom factor that depletes complement due to massive activation. Furthermore, C4BP was injected before and after the disease development into CIA mice. In the former case, the disease onset was delayed and in the latter, the severity of the disease was reduced in animals treated with C4BP. However, C4BP did not affect the anti-CII antibody synthesis. C4BP present in mouse sera decreased activity of the classical but not the alternative pathway of the complement system when these were assessed in a fluid phase. However, C4BP was efficiently inhibiting the alternative pathway when present on the activating surface. Taken together, the disease ameliorating effect of C4BP appears to be related to inhibition of both pathways of complement.Conclusions:Although human C4BP was cleared relatively fast from the circulation and was only moderately affecting complement activity, its effect on the disease severity was substantial, suggesting that minor alterations in complement activity can have significant therapeutic value in RA.

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Section: Resultsmentioning

confidence: 99%

C4b-binding protein (C4BP) inhibits development of experimental arthritis in mice

2008

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“…Moreover, ongoing research will enable assessment of the putative monocyte/DC surface receptor responsible for the tolerogenic activity of C4BP(b 2 ) isoforms. In that sense, it has been proposed that the CD40 receptor could bind directly C4BP on B cells inducing proliferation, overexpression of CD54 and CD86, and IL-4-dependent IgE isotype switching (22), or might bind indirectly C4BP, through interaction with CD40L, on cholangiocytes preventing apoptosis by interference with CD40-CD40L signaling in these cells (57). Our data extend the regulatory role of C4BP beyond preventing runaway complement activation and complement-mediated inflammation, because the activity of the C4BP(b 2 ) isoform on DCs could represent a regulatory feedback loop on adaptive immunity, avoiding excessive T cell activation to circumvent the consequent host tissue damage under acute proinflammatory conditions.…”

Section: Discussionmentioning

confidence: 99%

The α7β0 Isoform of the Complement Regulator C4b-Binding Protein Induces a Semimature, Anti-Inflammatory State in Dendritic Cells

Olivar

Luque

Naranjo-Gómez

et al. 2013

The Journal of Immunology

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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+CD127low/negCD25highFoxp3+ 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.

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“…Furthermore, whereas CD154 alone promotes and amplifies Fas-mediated hepatocyte and cholangiocyte apoptosis, the CD154/ C4BP complex, which binds efficiently to CD40, promotes survival by suppressing transcription factors required for induction of apoptosis. 112 These observations suggest that regulation of this pathway is even more complex than previously thought, with a role being played by other elements in the innate immune response.…”

Section: A Central Role For Cd40 In Regulating Immune-mediated Liver mentioning

confidence: 94%

Immune-Mediated Liver Injury

et al. 2007

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Diseases with different pathogeneses share common pathways of immune-mediated injury. Autoreactive T cells destroy hepatocytes or cholangiocytes in autoimmune disease and virus-specific T cells destroy infected hepatocytes in viral hepatitis. In these conditions, antigen-specific mechanisms can be implicated but immune-mediated injury is central to diseases where there is a less-defined role for specific antigens. In all these diseases, "bystander cells" activated by the local microenvironment rather than a specific antigen are major players and amplify effector responses by recruiting natural killer and natural killer T cells, macrophages, neutrophils, eosinophils, and even platelets. Immune-mediated liver injury is driven by repeated cycles of inflammation and damage sustained by continuing recruitment, retention, and survival of effector leukocytes within the inflamed liver. These processes depend on complex interactions involving epithelial cells, stromal cells, and leukocytes shaped by the local cytokine microenvironment. Understanding these interactions will elucidate the pathogenesis of liver disease and suggest new therapies.

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C4b Binding Protein Binds to CD154 Preventing CD40 Mediated Cholangiocyte Apoptosis: A Novel Link between Complement and Epithelial Cell Survival

Cited by 20 publications

References 36 publications

C4b-binding protein (C4BP) inhibits development of experimental arthritis in mice

C4b-binding protein (C4BP) inhibits development of experimental arthritis in mice

The α7β0 Isoform of the Complement Regulator C4b-Binding Protein Induces a Semimature, Anti-Inflammatory State in Dendritic Cells

Immune-Mediated Liver Injury

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