Publikationsdatenbank

A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages (2011)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Klotz, Christian

Ziegler, Thomas

Figueiredo, Ana Sofia

Rausch, Sebastian (WE 6)

Hepworth, Matthew R (WE 6)

Obsivac, Nadja

Sers, Christine

Lang, Roland

Hammerstein, Peter

Lucius, Richard

Hartmann, Susanne (WE 6)

Quelle

PLoS pathogens

Bandzählung: 7

Heftzählung: 1

Seiten: e1001248

ISSN: 1553-7374

Sprache

Englisch

Verweise

URL (Volltext): http://edocs.fu-berlin.de/docs/receive/FUDOCS_document_000000019823

DOI: 10.1371/journal.ppat.1001248

Pubmed: 21253577

Kontakt

Institut für Immunologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51834
immunologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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.