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Interleukin-10 contributes to PGE2 signalling through upregulation of EP4 via SHIP1 and STAT3

Abrar Samiea1,2, Jeff S J Yoon1,2,3, Sylvia T Cheung1,2,3

  • 1Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, Canada.

Plos One
|April 3, 2020
PubMed

Insights

Interleukin-10 (IL10) deactivates inflammatory macrophages via the IL10 receptor (IL10R) by upregulating the EP4 receptor. EP4 then activates cyclic adenosine monophosphate (cAMP) signaling, crucial for anti-inflammatory responses.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Macrophages are key immune cells involved in host defense against pathogens.
  • Activation of macrophages by lipopolysaccharide (LPS) leads to the production of inflammatory mediators.
  • Deactivation of activated macrophages is essential to prevent inflammatory diseases, with Interleukin-10 (IL10) playing a critical role.

Purpose of the Study:

  • To elucidate the signaling pathway through which IL10 deactivates activated macrophages.
  • To investigate the role of the IL10 receptor (IL10R) in macrophage deactivation.
  • To explore the connection between IL10 signaling and cyclic adenosine monophosphate (cAMP) pathways.

Main Methods:

  • Investigated IL10R signaling in macrophages.
  • Analyzed the expression of the EP4 receptor for prostaglandin E2 (PGE2).
  • Assessed the activation of downstream signaling molecules including cAMP, protein kinase A (PKA), and CREB.

Main Results:

  • IL10R signaling, dependent on STAT3/SHIP1, leads to increased expression of the EP4 receptor.
  • EP4 receptor activation in macrophages stimulates cAMP production and subsequent activation of PKA and CREB.
  • IL10-induced phosphorylation of CREB and inhibition of LPS-induced signaling require EP4 expression.

Conclusions:

  • IL10R activation enhances EP4 receptor expression via STAT3/SHIP1, which then activates cAMP-dependent signaling.
  • The EP4 receptor acts as a critical mediator linking IL10R to cAMP/PKA/CREB activation.
  • This coordinated signaling provides a mechanism for IL10-mediated macrophage deactivation and explains the synergy between IL10 and cAMP-elevating agents in anti-inflammatory responses.

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