P-STAT3 Inhibition Activates Endoplasmic Reticulum Stress-Induced Splenocyte Apoptosis in Chronic Stress
Open Access
- 30 June 2020
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Physiology
- Vol. 11, 680
- https://doi.org/10.3389/fphys.2020.00680
Abstract
Chronic stress leads to immunosuppression and induces splenocyte apoptosis. STAT3 is a transcription factor that regulates immunity and apoptosis; however, it is unclear whether the increased expression of phosphorylated STAT3 (p-STAT3) observed in chronic stress is related to splenocyte apoptosis. To explore the relationship between splenocyte apoptosis and STAT3 in chronic stress, we treated rats undergoing a 21-day chronic restraint stress program with the STAT3 inhibitor S3I-201. This chronic stress model was verified by observing rats’ behavior and measuring their serum corticosterone levels. Chronic stress led to increased expression of anti-inflammatory cytokines, and p-STAT3 inhibition enhanced splenocyte apoptosis in chronic stress. We detected key proteins in three apoptotic pathways to determine which pathway mediated increasing splenocyte apoptosis, and found that the death receptor pathway was the main apoptotic pathway that occurred in the spleen during chronic stress. The unfolded protein response (UPR) was also activated, but the Bcl-2 family was not involved in chronic stress. P-STAT3 inhibition had no influence on the Bcl-2 family and the death receptor pathway; however, p-STAT3 inhibition disrupted the pro-survival function of the UPR by decreasing the expression of ATF6α and p-IRE1α. Furthermore, p-STAT3 inhibition activated ER stress by promoting the expression of CHOP, p-JNK, and procaspase-12. Collectively, these findings indicate that the increased p-STAT3 expression during chronic stress may promote splenocyte survival by activating the UPR. Consequently, STAT3 and the UPR may be considered as potential therapeutic targets for chronic stress in the future.Keywords
Funding Information
- National Natural Science Foundation of China (编号C2017022, 第31772806号, 编号31802251)
This publication has 47 references indexed in Scilit:
- The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challengesBriefings in Functional Genomics, 2013
- STAT3 negatively regulates thyroid tumorigenesisProceedings of the National Academy of Sciences, 2012
- Chronic restraint stress attenuates p53 function and promotes tumorigenesisProceedings of the National Academy of Sciences, 2012
- Endoplasmic Reticulum Stress Inhibits STAT3-Dependent Suppression of Hepatic Gluconeogenesis via Dephosphorylation and DeacetylationDiabetes, 2011
- Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stressNature Cell Biology, 2011
- Transcriptional Induction of Mammalian ER Quality Control Proteins Is Mediated by Single or Combined Action of ATF6α and XBP1Developmental Cell, 2007
- Apoptosis: A Review of Programmed Cell DeathToxicologic Pathology, 2007
- Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activityProceedings of the National Academy of Sciences, 2007
- Stress and Health: Psychological, Behavioral, and Biological DeterminantsAnnual Review of Clinical Psychology, 2005
- The STATs of cancer — new molecular targets come of ageNature Reviews Cancer, 2004