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Insulin regulates macrophage activation through activin A

Joseph Cuschieri1, Eileen Bulger, Rebecca Grinsell

  • 1Department of Surgery, University of Washington, Seattle, Washington, USA. jcuschie@u.washington.edu

Shock (Augusta, Ga.)
|August 19, 2007
PubMed
Abstract

Insights

Insulin pretreatment attenuates endotoxin-induced macrophage activation by modulating the PI3K/AKT pathway and inflammatory mediator release. This effect involves activin A and SH2-containing inositol 5'-phosphatase (SHIP) regulation.

Area of Science:

  • Immunology
  • Cell Biology
  • Endocrinology

Background:

  • Strict glucose control with insulin may reduce multiple organ dysfunction syndrome by altering macrophage activation.
  • The PI3K/AKT pathway is a potential mechanism for insulin's effect on macrophages.
  • Understanding insulin's impact on endotoxin-mediated macrophage activation is crucial.

Purpose of the Study:

  • To investigate the role of the PI3K/AKT pathway in insulin's modulation of endotoxin-activated macrophages.
  • To elucidate the mechanism by which insulin affects macrophage activation.

Main Methods:

  • THP-1 cells were stimulated with endotoxin after insulin pretreatment.
  • Analysis of Toll-like receptor 4 signaling pathway components via immunoblot.
  • Measurement of TNF-alpha and IL-8 production using ELISA.
  • Assessment of transforming growth factor superfamily influence via receptor inhibition.

Main Results:

  • Endotoxin activated key signaling molecules (ERK1/2, p38, JNK), degraded IkappaB, activated NF-kappaB, and increased TNF-alpha and IL-8.
  • Insulin pretreatment delayed these endotoxin-induced inflammatory responses.
  • Insulin increased cytoplasmic SH2-containing inositol 5 -phosphatase (SHIP) and decreased lipid raft-bound SHIP.
  • Activin A blockade reversed insulin's effects on SHIP and endotoxin signaling.

Conclusions:

  • Insulin regulates macrophage response to endotoxin via activin A release and SHIP production.
  • Increased cytoplasmic SHIP by insulin attenuates endotoxin-mediated signaling and inflammatory mediator release.

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