The tumour suppressor gene p53 modulates the severity of antigen-induced arthritis and the systemic immune response

Abstract

Summaryp53 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 collageninduced 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)-g 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-g 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-cycleindependent mechanisms.

p53 Represses Class Switch Recombination to IgG2a through Its Antioxidant Function

“…The IgG2a isotype is involved in the pathology of most of the antibody-mediated autoimmune disease models in the mouse, so one can envision that limiting IgG2a switching might be beneficial. Aging p21-deficient animals develop autoimmune disease (69), and antigen-induced arthritis is more severe in p53−/− mice, without altering the antigen-specific Ig responses (70). Upon polyoma virus challenge, p53-deficient animals have significantly more IgG2a-expressing germinal center B cells in the spleen than polyoma-infected wild-type littermates, but this did not result in a measurable increase in virus-specific IgG2a titers in the serum (data not shown).…”

Absent in Melanoma 2 proteins in SLE

“…Accordingly, mice null for the Gadd45a [91] or p21 [92] gene (both genes are the transcriptional target of the p53 protein), develop lupus-like disease. Further, p53-deficient mice exhibited accelerated collagen-induced arthritis [93] and Ag-induced arthritis [94], an increased susceptibility to develop experimental autoimmune encephalomyelitis (EAE) [95] and autoimmune diabetes [96] than age-matched wild-type (p53 +/+ ) mice. Notably, p53-deficient macrophages produced more proinflammatory cytokines and expressed higher levels of activated STAT1 [96], thus suggesting that p53 protein inhibits autoimmunity in part by down-regulating the expression of IFN-inducible STAT1 and p202 proteins [89, 96].…”

The Double Role of p53 in Cancer and Autoimmunity and Its Potential as Therapeutic Target

“…Systemic p53-deficient mice develop more rapidly collagen-induced arthritis and antigen-induced arthritis [70,71]. These strains are also more susceptible to developing experimental autoimmune encephalomyelitis and streptozotocin (STZ)-induced diabetes in respect to control wild type mice [72,73].…”