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figueiredo2

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v_1

erk = erkp

v_10

X2 = X1 + Ap

v_11

extVar = IL10m

v_12

IL10m = extVar

v_13

extVar = IL10i

v_14

IL10i = extVar

v_15

IL10i = IL10e

v_16

IL10e = extVar

v_2

erkp = erk

v_3

p38 = p38p

v_4

p38p = p38

v_5

A = Ap

v_6

Ap = A

v_7

X0 = X1

v_8

X1 = X0

v_9

X1 + Ap = X2

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

  • Ana Sofia Figueiredo
  • Thomas Höfer
  • Christian Klotz
  • Christine Sers
  • Susanne Hartmann
  • Richard Lucius
  • Peter Hammerstein
FEBS J. 2009; 276 (13): 3454-3469
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.

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