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Prolonged Endoplasmic Reticulum-Stressed Hepatocytes Drive an Alternative Macrophage Polarization.

Shock (Augusta, Ga.) (2015-05-07)
Fangming Xiu, Michael Catapano, Li Diao, Mile Stanojcic, Marc G Jeschke
ABSTRACT

Relatively little is known about the effects of hepatocytes on hepatic macrophages, particularly under the situation of endoplasmic reticulum (ER) stress. We examined the effects of hepatocytes conditioned media (CM) from HepG2 treated with ER stress inducers, tunicamycin or thapsigargin, on the secretion of cytokines, expression of ER stress markers, and polarization of phorbol myristate acetate-activated THP-1 cells (pTHP-1). We found that CM decreased the production of the proinflammatory cytokines including tumor necrosis factor α, interleukin 6 (IL-6), and IL-1β as well as other cytokines and chemokines from pTHP-1 cells. These effects are mediated by the inhibition of TLR4 expression and nuclear factor κB signaling pathway. In addition, hepatocytes CM increased the expression of binding immunoglobulin protein and the transcription factor C/EBP homologous protein (CHOP) in pTHP-1 cells. Preconditioning with ER stress inhibitor, small molecular chaperone 4-phenylbutyrate before addition of ER stressors, attenuated the ER stress in macrophages, the property of hepatocytes CM to alter tumor necrosis factor α production and nuclear factor κB expression by macrophages. Remarkably, treatment of macrophage with these CM leads to an alternative activation of macrophages mediated by peroxisome proliferator-activated receptor γ signaling pathway, which might be resulted from the secretion of IL-10 and IL-4 as well as releasing apoptotic bodies from hepatocytes under ER stress. Our results highlight a mechanism of ER stress transmission from hepatocytes to macrophage that drives an alternative activation of macrophages, which depends on the exposure of hepatocytes to severe and prolonged ER stress.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Phorbol 12-myristate 13-acetate, ≥99% (TLC), film or powder
Sigma-Aldrich
PMA, for use in molecular biology applications, ≥99% (HPLC)
Sigma-Aldrich
Thapsigargin, ≥98% (HPLC), solid film
Sigma-Aldrich
Sodium palmitate, ≥98.5%
Sigma-Aldrich
Fluorescein, for fluorescence, free acid
Sigma-Aldrich
Fluorescein 5(6)-isothiocyanate, BioReagent, suitable for fluorescence, mixture of 2 components, ≥90% (HPLC)
Sigma-Aldrich
Phorbol 12-myristate 13-acetate, synthetic, ≥98.0% (TLC)
Sigma-Aldrich
Fluorescein 5(6)-isothiocyanate, ≥90% (HPLC)
Sigma-Aldrich
Fluorescein isothiocyanate isomer I, ≥97.5% (HPLC)
Sigma-Aldrich
Fluorescein isothiocyanate isomer I, ≥97.5% (HPLC)