UPR-mediated TRIB3 expression correlates with reduced AKT phosphorylation and inability of interleukin 6 to overcome palmitate-induced apoptosis in RINm5F cells.
Unfolded protein response (UPR)-mediated pancreatic beta-cell death has been described as a common mechanism by which palmitate (PA) and pro-inflammatory cytokines contribute to the development of diabetes. There are evidences that interleukin 6 (IL6) has a protective action against beta-cell death induced by pro-inflammatory cytokines; the effects of IL6 on PA-induced apoptosis have not been investigated yet. In the present study, we have demonstrated that PA selectively disrupts IL6-induced RAC-alpha serine/threonine-protein kinase (AKT) activation without interfering with signal transducer and activator of transcription 3 phosphorylation in RINm5F cells. The inability of IL6 to activate AKT in the presence of PA correlated with an inefficient protection against PA-induced apoptosis. In contrast to PA, IL6 efficiently reduced apoptosis induced by pro-inflammatory cytokines. In addition, we have demonstrated that IL6 is unable to overcome PA-stimulated UPR, as assessed by activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression, X-box binding protein-1 gene mRNA splicing, and pancreatic eukaryotic initiation factor-2 alpha kinase phosphorylation, whereas no significant induction of UPR by pro-inflammatory cytokines was detected. This unconditional stimulation of UPR and apoptosis by PA was accompanied by the stimulation of CHOP and tribble3 (TRIB3) expression, irrespective of the presence of IL6. These findings suggest that IL6 is unable to protect pancreatic beta-cells from PA-induced apoptosis because it does not repress UPR activation. In this way, CHOP and ATF4 might mediate PA-induced TRIB3 expression and, by extension, the suppression of IL6 activation of pro-survival kinase AKT.
Nicoletti-Carvalho
José Edgar
JE
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Prof. Lineu Prestes Ave #1524, 05508-900 Sao Paulo, SP, Brazil.
Nogueira
Tatiane C Araújo
TC
Gorjão
Renata
R
Bromati
Carla Rodrigues
CR
Yamanaka
Tatiana S
TS
Boschero
Antonio Carlos
AC
Velloso
Licio Augusto
LA
Curi
Rui
R
Anhê
Gabriel Forato
GF
Bordin
Silvana
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053938:DNA Fragmentation; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D049669:History, 16th Century; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D007340:Insulinoma / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D010168:Palmitates / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D056811:Unfolded Protein Response
D015850:Interleukin-6; D010168:Palmitates; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; C502443:Trib3 protein, rat; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3