title: The tumour suppressor gene p53 modulates the severity of antigen-induced arthritis and the systemic immune response.
abstract: p53 is a transcription factor with a well-described role in the induction of apoptosis and cell cycle arrest as part of a protective response to a variety of stressful stimuli. Expansion of inflamed tissue in rheumatoid arthritis has been related to the loss of functioning p53, and the severity of collagen-induced arthritis is increased in p53-/- mice. Our objective was to assess the role of p53 in a model of adaptive immunity, antigen-induced arthritis (AIA). AIA was induced in p53-/- and wild-type mice by priming with methylated bovine serum albumin followed by intra-articular challenge. Severity of arthritis was assessed using a standardized scoring system and synovial apoptosis was detected by TdT-mediated biotin-dUTP nick-end labelling. Splenocyte proliferation was measured by [H(3)] incorporation and interferon (IFN)-gamma release. Splenocyte viability was assessed using Titreglow. Splenic T cell activation status was assessed by flow cytometry. Serum cytokines were measured using enzyme-linked immunosorbent assay. Increased severity of AIA in p53-/- mice was associated with decreased synovial apoptosis and with increased delayed-type hypersensitivity response, increased mitogen and antigen-induced splenocyte proliferation and increased IFN-gamma release in p53-/- mice compared with wild-type mice. Antigen-specific immunoglobulin responses were equivalent in both groups. Splenocyte viability was increased in p53-/- mice but T cell apoptosis was equivalent. T cell activation markers were increased in p53-/- mice compared with wild-type mice. Lipopolysaccharide-induced tumour necrosis factor release was increased in p53-/- mice with a trend to increased interleukin-6 in p53-/- mice compared with littermates. p53 is involved in the modulation of adaptive and innate immune responses relevant to arthritis models and is also involved in the modulation of severity of AIA by both cell-cycle dependent and cell-cycle-independent mechanisms.
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Melbourne, Australia. michelle.leech@med.monash.edu.au
authors.forename: M
authors.initials: M
authors.lastname: Leech
authors.forename: J R
authors.initials: JR
authors.lastname: Xue
authors.forename: A
authors.initials: A
authors.lastname: Dacumos
authors.forename: P
authors.initials: P
authors.lastname: Hall
authors.forename: L
authors.initials: L
authors.lastname: Santos
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.forename: A R
authors.initials: AR
authors.lastname: Kitching
authors.forename: E F
authors.initials: EF
authors.lastname: Morand
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D016158:Genes, p53 / Q000276:immunology*; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010835:Phytohemagglutinins / Q000276:immunology; D012710:Serum Albumin, Bovine / Q000276:immunology; D012720:Severity of Illness Index; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000276:immunology
chemical_list: D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D010835:Phytohemagglutinins; D016159:Tumor Suppressor Protein p53; C029180:methylated bovine serum albumin; D012710:Serum Albumin, Bovine; D007371:Interferon-gamma