Mice Lacking the p53-Effector Gene Gadd45a Develop a Lupus-Like Syndrome

During the pathogenesis of rheumatoid arthritis (RA), the synovial fibroblasts increase in number and produce proinflammatory cytokines and matrix metalloproteinases (MMPs) that function to promote inflammation and joint destruction. Recent investigations have suggested that cell cycle activity and inflammation may be linked. However, little is known about the mechanisms responsible for the coordinate regulation of proliferation and the expression of proinflammatory molecules in RA synovial fibroblasts. Here, we demonstrate a 50 ± 10% decrease in the expression of p21, a cell cycle inhibitor, in the synovial fibroblast population from RA compared with osteoarthritis (OA) synovial tissue. Moreover, p21 positivity in the synovial fibroblasts inversely correlates with medium synovial lining thickness (r = −0.76; p < 0.02). The expression of p21 is also reduced in isolated RA synovial fibroblasts compared with OA synovial fibroblasts. Adenovirus-mediated delivery of p21 (Ad-p21) arrests both RA and OA synovial fibroblasts in the G0/G1 phase of the cell cycle without inducing cytotoxicity. However, the spontaneous production of IL-6 and MMP-1 is suppressed only in the Ad-p21-infected RA synovial fibroblasts, indicating a novel role for p21 in RA. Analyses of p21-deficient mouse synovial fibroblasts reveal a 100-fold increase in IL-6 protein and enhance IL-6 and MMP-3 mRNA. Restoration of p21, but not overexpression of Rb, which also induces G0/G1 cell cycle arrest, decreases IL-6 synthesis in p21-null synovial fibroblasts. Furthermore, in RA synovial fibroblasts the ectopic expression of p21 reduces activation of the AP-1 transcription factor. Additionally, p21-null synovial fibroblasts display enhanced activation of AP-1 compared with wild-type synovial fibroblasts. These data suggest that alterations in p21 expression may activate AP-1 leading to enhanced proinflammatory cytokine and MMP production and development of autoimmune disease.

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“…Recent investigations have demonstrated that mice deficient for p21 exhibit lupus-like disease at 9 mo of age (65,66). However, it FIGURE 9.…”

Section: Discussionmentioning

confidence: 99%

IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts

Perlman

Bradley

Liu

et al. 2003

The Journal of Immunology

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“…This enhances catalytic activity and subsequent autophosphorylation on the canonical activating residues Thr 180 /Tyr 182 (15). Lack of Gadd45␣ results in constitutively active T cell p38, hyperproliferation in response to TCR-mediated signals, and development of a lupus-like autoimmune disease (16,17). Because loss of Gadd45␣ results in spontaneous ZAP70-mediated T cell p38 activity (17) but decreased MAP kinase cascade-mediated p38 activity in stress or oncogeneactivated nonimmune cells (fibroblasts and keratinocytes; Refs.…”

Section: Gadd45␣ Regulates P38-dependent Dendritic Cell Cytokinementioning

confidence: 99%

Gadd45α Regulates p38-Dependent Dendritic Cell Cytokine Production and Th1 Differentiation

Jirmanova

Janković

Fornace

et al. 2007

The Journal of Immunology

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Gadd45α inhibits the activation of p38 by the T cell alternative pathway involving phosphorylation of p38 Tyr323. Given that T cell p38 may play a role in Th1 development, the response to Th-skewing Ags was analyzed in Gadd45α−/− mice. Despite constitutively increased p38 activity in Gadd45α−/− T cells, the Th1 immune response to Toxoplasma gondii Ag (STAg), was diminished. In contrast to T cells, dendritic cells (DC) lacked the alternative p38 activation pathway. Gadd45α−/− DCs responded to STAg with low levels of MAP kinase cascade-dependent p38 activation, IL-12 production, and CD40 expression. Wild-type T cells transferred into Gadd45α−/− recipients had a diminished Th1 response to STAg, whereas Gadd45α−/− T cells transferred into wild-type hosts behaved normally. Therefore, Gadd45α has tissue-specific and opposing functions on p38 activity, and Gadd45α-regulated p38 activation in DCs is a critical event in Th1 polarization in vivo.

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“…17 Multiple types of human lymphoproliferative/autoimmune disease have been associated with increased incidence of lymphomas (reviewed in Ehrenfeld et al 18 ), and HTLVI infection can lead to both autoimmune disease and lymphoma. 19 Therefore, the presence of autoimmune disease in Gadd45aÀ/À mice may be a contributing factor to lymphomagenesis in the presence of additional tumor-promoting stimuli.…”

Section: Discussionmentioning

confidence: 99%