title: Modelling and simulating interleukin-10 production and regulation by macrophages after stimulation with an immunomodulator of parasitic nematodes.
abstract: Parasitic nematodes can downregulate the immune response of their hosts through the induction of immunoregulatory cytokines such as interleukin-10 (IL-10). To define the underlying mechanisms, we measured in vitro the production of IL-10 in macrophages in response to cystatin from Acanthocheilonema viteae, an immunomodulatory protein of filarial nematodes, and developed mathematical models of IL-10 regulation. IL-10 expression requires stimulation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and p38, and we propose that a negative feedback mechanism, acting at the signalling level, is responsible for transient IL-10 production that can be followed by a sustained plateau. Specifically, a model with negative feedback on the ERK pathway via secreted IL-10 accounts for the experimental data. Accordingly, the model predicts sustained phospho-p38 dynamics, whereas ERK activation changes from transient to sustained when the concentration of immunomodulatory protein of Acanthocheilonema viteae increases. We show that IL-10 can regulate its own production in an autocrine fashion, and that ERK and p38 control IL-10 amplitude, duration and steady state. We also show that p38 affects ERK via secreted IL-10 (autocrine crosstalk). These findings demonstrate how convergent signalling pathways may differentially control kinetic properties of the IL-10 signal.
authors.affiliation: Institute for Theoretical Biology, Humboldt University, Berlin, Germany. s.figueiredo@biologie.hu-berlin.de
authors.forename: Ana Sofia
authors.initials: AS
authors.lastname: Figueiredo
authors.forename: Thomas
authors.initials: T
authors.lastname: Höfer
authors.forename: Christian
authors.initials: C
authors.lastname: Klotz
authors.forename: Christine
authors.initials: C
authors.lastname: Sers
authors.forename: Susanne
authors.initials: S
authors.lastname: Hartmann
authors.forename: Richard
authors.initials: R
authors.lastname: Lucius
authors.forename: Peter
authors.initials: P
authors.lastname: Hammerstein
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D015891:Cystatins / Q000276:immunology; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D004153:Dipetalonema / Q000276:immunology / Q000472:pathogenicity; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D015801:Helminth Proteins / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008962:Models, Theoretical; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015891:Cystatins; D015853:Cysteine Proteinase Inhibitors; D015801:Helminth Proteins; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases