| First Author | Zhang S | Year | 2011 |
| Journal | FASEB J | Volume | 25 |
| Issue | 7 | Pages | 2387-98 |
| PubMed ID | 21471252 | Mgi Jnum | J:174321 |
| Mgi Id | MGI:5056259 | Doi | 10.1096/fj.10-175299 |
| Citation | Zhang S, et al. (2011) Trp53 negatively regulates autoimmunity via the STAT3-Th17 axis. FASEB J 25(7):2387-98 |
| abstractText | Emerging evidence suggests that the tumor suppressor p53 is also a crucial regulator for many physiological processes. Previous observations indicate that p53 suppresses inflammation by inhibiting inflammatory antigen-presenting cells. To investigate the potential role of p53 in autoimmune effector T cells, we generated p53(null)CD45.1 mice by crossing p53(null)CD45.2 and CD45.1 mice. We demonstrate that p53(null)CD45.1 mice spontaneously developed autoimmunity, with a significant increase in IL-17-producing Th17 effectors in their lymph nodes (4.7+/-1.0%) compared to the age-matched counterparts (1.9+/-0.8% for p53(null)CD45.2, 1.1+/-0.2% for CD45.1, and 0.5+/-0.1% for CD45.2 mice). Likewise, p53(null)CD45.1 mice possess highly elevated serum levels of inflammatory cytokines IL-17 and IL-6. This enhanced Th17 response results largely from an increased sensitivity of p53(null)CD45.1 T cells to IL-6-induced STAT3 phosphorylation. Administration of STAT3 inhibitor S31-201 (IC50 of 38.0+/-7.2 muM for IL-6-induced STAT3 phosphorylation), but not PBS control, to p53(null)CD45.1 mice suppressed Th17 effectors and alleviated autoimmune pathology. This is the first report revealing that p53 activity in T cells suppresses autoimmunity by controlling Th17 effectors. This study suggests that p53 serves as a guardian of immunological functions and that the p53-STAT3-Th17 axis might be a therapeutic target for autoimmunity.-Zhang, S., Zheng, M., Kibe, R., Huang, Y., Marrero, L., Warren, S., Zieske, A. W., Iwakuma, T., Kolls, J. K., Cui, Y. Trp53 negatively regulates autoimmunity via the STAT3-Th17 axis. |
