Modelling and simulating interleukin-10 production and regulation by macrophages after stimulation with an immunomodulator of parasitic nematodes

FEBS J. 2009 Jul;276(13):3454-69. doi: 10.1111/j.1742-4658.2009.07068.x. Epub 2009 May 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autocrine Communication / physiology*
  • Cystatins / immunology
  • Cysteine Proteinase Inhibitors / metabolism
  • Dipetalonema* / immunology
  • Dipetalonema* / pathogenicity
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation
  • Helminth Proteins / genetics
  • Helminth Proteins / immunology*
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism*
  • MAP Kinase Signaling System / physiology*
  • Macrophages / cytology
  • Macrophages / immunology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Theoretical*
  • Phosphorylation
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cystatins
  • Cysteine Proteinase Inhibitors
  • Helminth Proteins
  • Interleukin-10
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases