dc.contributor.author
Klotz, Christian
dc.contributor.author
Ziegler, Thomas
dc.contributor.author
Figueiredo, Ana Sofia
dc.contributor.author
Rausch, Sebastian
dc.contributor.author
Hepworth, Matthew R.
dc.contributor.author
Obsivac, Nadja
dc.contributor.author
Sers, Christine
dc.contributor.author
Lang, Roland
dc.contributor.author
Hammerstein, Peter
dc.contributor.author
Lucius, Richard
dc.contributor.author
Hartmann, Susanne
dc.date.accessioned
2018-06-08T03:19:12Z
dc.date.available
2014-03-07T10:43:46.037Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/14906
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-19094
dc.description.abstract
Parasitic worms alter their host's immune system to diminish the inflammatory
responses directed against them, using very efficient immunomodulating
molecules. We have previously shown that the helminth immunomodulator cystatin
(AvCystatin) profoundly reduces the progression of inflammatory diseases via
modulation of macrophages. Here we elucidate the signaling events in
macrophages triggered by AvCystatin. Labeled AvCystatin was predominantly
taken up by macrophages and subsequently induced the phosphorylation of the
mitogen-activated protein kinases (MAPK) ERK1/2 and p38. IL-10 expression
induced by AvCystatin in macrophages was tyrosine kinase sensitive and
dependent on activation of both MAP kinases, in clear contrast to expression
of IL-12/23p40. In addition, phosphorylation of the transcription factors CREB
and STAT3 was induced by AvCystatin and regulated by phospho-ERK. Chemical
inhibition of phosphoinositide 3-kinase (PI3K) reduced AvCystatin-induced
cytokine release; however, AKT, the downstream target of PI3K, was not
activated following AvCystatin exposure. To characterize signaling elements
involved in alteration of the macrophage phenotype we applied mathematical
modeling. Experimental testing of the in silico generated hypotheses
identified dual specificity phosphatase (DUSP) 1 and 2, as regulators in
AvCystatin triggered macrophages in vitro and in vivo. In particular, DUSP1
was subsequently found to be responsible for regulation of ERK- and
p38-phosphorylation and controlled the IL-10 expression in macrophages by
AvCystatin. Thus, we show that AvCystatin exploits activation and deactivation
pathways of MAP kinases to induce regulatory macrophages. This study provides
insights into molecular mechanisms of macrophage manipulation by parasites and
highlights the utility of mathematical modeling for the elucidation of
regulatory circuits of immune cells.
en
dc.rights.uri
http://creativecommons.org/licenses/by/2.5/
dc.subject.ddc
500 Naturwissenschaften und Mathematik::530 Physik
dc.title
A Helminth Immunomodulator Exploits Host Signaling Events to Regulate Cytokine
Production in Macrophages
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation
PLoS Pathogens; 7(2011), 1, Artikel Nr. e1001248/1-17
dcterms.bibliographicCitation.doi
10.1371/journal.ppat.1001248
dcterms.bibliographicCitation.url
http://dx.doi.org/10.1371/journal.ppat.1001248
refubium.affiliation
Veterinärmedizin
de
refubium.affiliation.other
Institut für Immunologie und Molekularbiologie
refubium.mycore.fudocsId
FUDOCS_document_000000019823
refubium.note.author
Der Artikel wurde in einer Open-Access-Zeitschrift publiziert.
refubium.resourceType.isindependentpub
no
refubium.mycore.derivateId
FUDOCS_derivate_000000003189
dcterms.accessRights.openaire
open access