Trp53 negatively regulates autoimmunity via the STAT3-Th17 axis

Shuzhong Zhang, Mingquan Zheng, Ryoko Kibe, Yunping Huang, Luis Marrero, Samantha Warren, Arthur W. Zieske, Tomoo Iwakuma, Jay K. Kolls, Yan Cui

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

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 nullCD45.1 mice by crossing p53 nullCD45.2 and CD45.1 mice. We demonstrate that p53 nullCD45.1 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 nullCD45.2, 1.1±0.2% for CD45.1, and 0.5±0.1% for CD45.2 mice). Likewise, p53 nullCD45.1 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 nullCD45.1 T cells to IL-6-induced STAT3 phosphorylation. Administration of STAT3 inhibitor S31-201 (IC50 of 38.0±7.2 μM for IL-6-induced STAT3 phosphorylation), but not PBS control, to p53 nullCD45.1 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.

Original languageEnglish (US)
Pages (from-to)2387-2398
Number of pages12
JournalFASEB Journal
Volume25
Issue number7
DOIs
StatePublished - Jul 2011

Keywords

  • CD45.1
  • IL-17
  • IL-6
  • Inflammatory cytokines

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Zhang, S., Zheng, M., Kibe, R., Huang, Y., Marrero, L., Warren, S., Zieske, A. W., Iwakuma, T., Kolls, J. K., & Cui, Y. (2011). Trp53 negatively regulates autoimmunity via the STAT3-Th17 axis. FASEB Journal, 25(7), 2387-2398. https://doi.org/10.1096/fj.10-175299