The alpha(7)beta(0) Isoform of the Complement Regulator C4b-Binding Protein Induces a Semimature, Anti-Inflammatory State in Dendritic Cells
Olivar, Rut ; Luque, Ana ; Naranjo-Gomez, Mar ; Quer, Josep ; Garcia de Frutos, Pablo LU ; Borras, Francesc E. ; Rodriguez de Cordoba, Santiago ; Blom, Anna LU
and Aran, Josep M.
(2013)
In Journal of Immunology
190(6).
p.2857-2872
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3651236
- author
- Olivar, Rut
; Luque, Ana
; Naranjo-Gomez, Mar
; Quer, Josep
; Garcia de Frutos, Pablo
LU
; Borras, Francesc E.
; Rodriguez de Cordoba, Santiago
; Blom, Anna
LU
and Aran, Josep M.
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Immunology
- volume
- 190
- issue
- 6
- pages
- 2857 - 2872
- publisher
- American Association of Immunologists
- external identifiers
-
- wos:000315657200042
- scopus:84874842539
- pmid:23390292
- ISSN
- 1550-6606
- DOI
- 10.4049/jimmunol.1200503
- language
- English
- LU publication?
- yes
- id
- 3c541258-629c-49ad-9fa2-54e5d7ff0565 (old id 3651236)
- date added to LUP
- 2016-04-01 14:32:46
- date last changed
- 2022-04-30 02:24:22
@article{3c541258-629c-49ad-9fa2-54e5d7ff0565,
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.}},
author = {{Olivar, Rut and Luque, Ana and Naranjo-Gomez, Mar and Quer, Josep and Garcia de Frutos, Pablo and Borras, Francesc E. and Rodriguez de Cordoba, Santiago and Blom, Anna and Aran, Josep M.}},
issn = {{1550-6606}},
language = {{eng}},
number = {{6}},
pages = {{2857--2872}},
publisher = {{American Association of Immunologists}},
series = {{Journal of Immunology}},
title = {{The alpha(7)beta(0) Isoform of the Complement Regulator C4b-Binding Protein Induces a Semimature, Anti-Inflammatory State in Dendritic Cells}},
url = {{http://dx.doi.org/10.4049/jimmunol.1200503}},
doi = {{10.4049/jimmunol.1200503}},
volume = {{190}},
year = {{2013}},
}