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Published online before print April 21, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1104685

Received for publication November 23, 2004.
Revised March 2, 2005.
Accepted for publication March 29, 2005.

Article

Up-regulation of GRP78 and antiapoptotic signaling in murine peritoneal macrophages exposed to insulin

Department of Pathology, Duke University Medical Center, Durham, North Carolina

^@ To whom correspondence should be addressed. E-mail: Pizzo001{at}mc.duke.edu.

	Abstract

The unfolded protein response pathway (UPR) compensates for excessive protein accumulation in the endoplasmic reticulum (ER). As insulin induces global protein synthesis, it may cause accumulation of unfolded proteins in the ER, thus triggering UPR. We assessed UPR activation in insulin-treated murine peritoneal macrophages using a number of markers including 78 kDa glucose response protein (GRP78), X-box-binding protein (XBP)-1, pancreatic ER kinase (PERK), eukaryotic initiation factor 2 (eIF2), and growth arrest and DNA damage (GADD)34. Exposure of cells to insulin activated UPR, as evidenced by an increased expression of GRP78, XBP-1, phosphorylated PERK (p-PERK), and p-eIF2. The insulin-induced, elevated expression of GRP78 was comparable with that observed with tunicamycin, a classical inducer of ER stress. Concomitantly, insulin also up-regulated prosurvival mechanisms by elevating GADD34 and elements of the antiapoptotic pathway including Bcl-2, X-linked inhibitor of apoptosis, and phosphorylated forkhead transcription factor. In conclusion, we show here that insulin treatment does cause ER stress in macrophages, but insulin-dependent mechanisms overcome this ER stress by up-regulating UPR and the antiapoptotic pathway to promote cell survival.

Key Words: unfolded protein response • apoptosis • Akt • FKHR • CREB • regulation of protein synthesis • endoplasmic reticulum • regulation of protein catabolism

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