title: Trp53 negatively regulates autoimmunity via the STAT3-Th17 axis.
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(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 μM 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.
authors.affiliation: Gene Therapy Program, Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, 533 Bolivar St., New Orleans, LA 70112, USA.
authors.forename: Shuzhong
authors.initials: S
authors.lastname: Zhang
authors.forename: Mingquan
authors.initials: M
authors.lastname: Zheng
authors.forename: Ryoko
authors.initials: R
authors.lastname: Kibe
authors.forename: Yunping
authors.initials: Y
authors.lastname: Huang
authors.forename: Luis
authors.initials: L
authors.lastname: Marrero
authors.forename: Samantha
authors.initials: S
authors.lastname: Warren
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Zieske
authors.forename: Tomoo
authors.initials: T
authors.lastname: Iwakuma
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.forename: Yan
authors.initials: Y
authors.lastname: Cui
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse