T cell-specific BLIMP-1 deficiency exacerbates experimental autoimmune encephalomyelitis in nonobese diabetic mice by increasing Th1 and Th17 cells.

Recently, we demonstrated that B lymphocyte-induced maturation protein 1 (BLIMP-1) has a role in regulating the differentiation and effector function of Th1 and Th17 cells. As these cells play critical roles in the induction and pathogenesis of experimental autoimmune encephalomyelitis (EAE), we investigated the potential role of T cell BLIMP-1 in modulating MOG35-55-induced EAE. We established T cell-specific BLIMP-1 conditional knockout (CKO) NOD mice to dissect the role of BLIMP-1 in EAE using loss-of-function model. Our results indicate that EAE severity is dramatically exacerbated in CKO mice. The numbers of CNS-infiltrating Th1, Th17, IFN-γ(+)IL-17A(+), and IL-21(+)IL-17A(+) CD4(+) T cells are remarkably increased in brain and spinal cord of CKO mice. Moreover, the ratio of Tregs/effectors and IL-10 production of Tregs are significantly downregulated in CNS of CKO mice. We conclude that BLIMP-1 suppresses autoimmune encephalomyelitis via downregulating Th1 and Th17 cells and impairing Treg cells.

Nonsteroidal anti-inflammatory drugs induced endothelial apoptosis by perturbing peroxisome proliferator-activated receptor-delta transcriptional pathway.

Recent studies have shown that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of myocardial infarction. To explore whether NSAIDs may induce endothelial apoptosis and thereby enhance atherothrombosis, we treated human umbilical vein endothelial cells (HUVECs) with sulindac sulfide (SUL), indomethacin (IND), aspirin (ASA), or sodium salicylate (NaS), and we analyzed apoptosis. SUL and/or IND significantly increased annexin V-positive cells, cleaved poly(ADP-ribose) polymerase (PARP) and caspase-3. ASA and NaS at 1 mM did not induce PARP cleavage or caspase-3 and at 5 mM, ASA but not NaS increased apoptosis. Because peroxisome proliferator-activated receptor delta-mediated 14-3-3epsilon up-regulation was reported to play a crucial role in protecting against apoptosis, we determined whether NSAIDs suppress this transcriptional pathway. SUL, IND, and ASA (5 mM) suppressed PPARdelta and 14-3-3 proteins in a manner parallel to PARP cleavage. Neither ASA nor NaS at 1 mM interfered with PPARdelta or 14-3-3epsilon expression. SUL inhibited PPARdelta promoter activity, which correlated with 14-3-3epsilon promoter suppression. Suppression of 14-3-3epsilon was associated with increased Bad translocation to mitochondria. Neither carbaprostacylin nor 4-(3-(2-propyl-3-hydroxy-4-acetyl)-phenoxy)propyloxyphenoxy acetic acid (L-165041) prevented HUVECs from SUL-induced apoptosis. Because of suppression of ectopic PPARdelta by sulindac, adenoviral PPARdelta transduction failed to restore 14-3-3epsilon or prevent PPAR cleavage. Our findings suggest that NSAIDs, but not aspirin (<1 mM) induce endothelial apoptosis via suppression of PPARdelta-mediated 14-3-3epsilon expression.