Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of 
the tumor necrosis factor superfamily, whose members are capable of inducing 
apoptosis and inflammation. Endoplasmic reticulum stress (ERS) plays a key role 
in immune surveillance in macrophages. TRAIL mRNA and protein expression have 
previously been detected in macrophages; however, whether ERS has any effects on 
TRAIL expression in macrophages has not yet been determined. Here, we 
demonstrate that thapsigargin (TG) and tunicamycin (TM), two ERS inducers 
activated macrophages were able to increase TRAIL mRNA and protein expression in 
RAW264.7 macrophages, the culture supernatant of THP-1 cells, and mouse 
peritoneal macrophages, indicating that ERS as a potent inducer of TRAIL 
transcription and expression in macrophages. This effect was blocked by the 
specific JNK inhibitor SP600125 and transcription factor AP-1 inhibitor SR 1130. 
Interestingly, at the molecular level, regulation of TRAIL expression by ERS was 
accompanied by a significant decrease in cytokine signaling suppressor 3 
(SOCS3). SOCS3 siRNA clearly increased the expression of TRAIL mRNA and protein 
under ERS by activating the AP-1 components phosphorylated c-Jun and 
phosphorylated c-Fos in RAW264.7 cells. In contrast, over-expression of SOCS3 
reversed ERS-induced TRAIL expression. These findings provide in vitro evidence 
that SOCS3 plays a critical negative role in the regulation of ERS-induced TRAIL 
expression via the Jun N-terminal kinase/AP-1 signaling pathway in macrophages.