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

25 Citations (Scopus)

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 1 2011
Externally publishedYes

Fingerprint

T-cells
Autoimmunity
Interleukin-6
Phosphorylation
Interleukin-17
Pathology
T-Lymphocytes
Tumors
Physiological Phenomena
Cytokines
Antigen-Presenting Cells
Inhibitory Concentration 50
Lymph Nodes
Inflammation
Serum
Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Zhang, S., Zheng, M., Kibe, R., Huang, Y., Marrero, L., Warren, S., ... 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

Trp53 negatively regulates autoimmunity via the STAT3-Th17 axis. / Zhang, Shuzhong; Zheng, Mingquan; Kibe, Ryoko; Huang, Yunping; Marrero, Luis; Warren, Samantha; Zieske, Arthur W.; Iwakuma, Tomoo; Kolls, Jay K.; Cui, Yan.

In: FASEB Journal, Vol. 25, No. 7, 01.07.2011, p. 2387-2398.

Research output: Contribution to journalArticle

Zhang, S, Zheng, M, Kibe, R, Huang, Y, Marrero, L, Warren, S, Zieske, AW, Iwakuma, T, Kolls, JK & Cui, Y 2011, 'Trp53 negatively regulates autoimmunity via the STAT3-Th17 axis', FASEB Journal, vol. 25, no. 7, pp. 2387-2398. https://doi.org/10.1096/fj.10-175299
Zhang S, Zheng M, Kibe R, Huang Y, Marrero L, Warren S et al. Trp53 negatively regulates autoimmunity via the STAT3-Th17 axis. FASEB Journal. 2011 Jul 1;25(7):2387-2398. https://doi.org/10.1096/fj.10-175299
Zhang, Shuzhong ; Zheng, Mingquan ; Kibe, Ryoko ; Huang, Yunping ; Marrero, Luis ; Warren, Samantha ; Zieske, Arthur W. ; Iwakuma, Tomoo ; Kolls, Jay K. ; Cui, Yan. / Trp53 negatively regulates autoimmunity via the STAT3-Th17 axis. In: FASEB Journal. 2011 ; Vol. 25, No. 7. pp. 2387-2398.
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