A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages.

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 dis...

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Autores principales:	Christian Klotz, Thomas Ziegler, Ana Sofia Figueiredo, Sebastian Rausch, Matthew R Hepworth, Nadja Obsivac, Christine Sers, Roland Lang, Peter Hammerstein, Richard Lucius, Susanne Hartmann
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/70c47a51d7c54e9fb9f594f35f8aaad3
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spelling	oai:doaj.org-article:70c47a51d7c54e9fb9f594f35f8aaad32021-11-18T06:03:41ZA helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages.1553-73661553-737410.1371/journal.ppat.1001248https://doaj.org/article/70c47a51d7c54e9fb9f594f35f8aaad32011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21253577/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Parasitic 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.Christian KlotzThomas ZieglerAna Sofia FigueiredoSebastian RauschMatthew R HepworthNadja ObsivacChristine SersRoland LangPeter HammersteinRichard LuciusSusanne HartmannPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 7, Iss 1, p e1001248 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Christian Klotz Thomas Ziegler Ana Sofia Figueiredo Sebastian Rausch Matthew R Hepworth Nadja Obsivac Christine Sers Roland Lang Peter Hammerstein Richard Lucius Susanne Hartmann A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages.
description	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.
format	article
author	Christian Klotz Thomas Ziegler Ana Sofia Figueiredo Sebastian Rausch Matthew R Hepworth Nadja Obsivac Christine Sers Roland Lang Peter Hammerstein Richard Lucius Susanne Hartmann
author_facet	Christian Klotz Thomas Ziegler Ana Sofia Figueiredo Sebastian Rausch Matthew R Hepworth Nadja Obsivac Christine Sers Roland Lang Peter Hammerstein Richard Lucius Susanne Hartmann
author_sort	Christian Klotz
title	A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages.
title_short	A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages.
title_full	A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages.
title_fullStr	A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages.
title_full_unstemmed	A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages.
title_sort	helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/70c47a51d7c54e9fb9f594f35f8aaad3
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A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages.

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