PARP-1 in Juvenile Idiopathic Arthritis-associated IL-10 Promoter Polymorphisms

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DESCRIPTION (provided by applicant): ABSTRACT: Juvenile idiopathic arthritis (JIA) is the most common chronic autoimmune inflammatory disease in childhood. Lower IL-10 production in patients with the -1082A/-819T/-592A (ATA) IL-10 promoter genotype can lead to excessive inflammatory responses with more severe arthritis, suggesting a direct association of IL-10 gene variants with JIA. Recently, we identified poly(ADP-ribose) polymerase 1 (PARP-1) as a novel transcriptional repressor of IL-10 gene expression with enhanced binding affinity for the ATA IL-10 promoter genotype. Therefore, we hypothesize that PARP-1-mediated suppression of IL-10 production is important for the pathogenesis of JIA, and that removing this suppression could result in effective therapies for treating patients with JIA. IL-10 is a pleiotropic cytokine produced by a variety of immune cells including T cells, B cells, macrophages and dendritic cells. It inhibits the production of proinflammatory cytokines and suppresses the effects of proinflammatory cytokines such as tumor necrosis factor-a (TNF-a). PARP-1 is a highly conserved nuclear zinc- finger protein involved in DNA repair, chromatin decondensation and gene expression. Our recent work has demonstrated that PARP-1 binding to the IL-10 promoter is enhanced by the -592A sequence polymorphism, and that over-expression of PARP-1 results in lower IL-10 production in human macrophages. However, the mechanistic details of how IL-10 is regulated by PARP-1 are unknown, and must be elucidated in order to develop new therapies based on targeting PARP-1. Therefore, in this project, we will: (1) elucidate the mechanistic detail of how PARP-1 regulates IL-10 gene expression at the molecular level. (2) develop methods capable of reversing PARP-1-mediated suppression of IL-10 production in JIA patients expressing the ATA IL-10 promoter genotype. This study will enable us to identify key steps in the regulatory pathway that may be explored as potential targets of therapeutic intervention in JIA. Moreover, the proposed investigation into ways to inhibit PARP-1 activity in JIA patients' blood cells of the susceptible type may eventually help correct their IL-10 production deficit, thus restoring the patients' own immune capacity to control arthritic inflammation. PUBLIC HEALTH RELEVANCE: RELEVANCE Elucidation of the molecular mechanisms whereby PARP-1 regulates IL-10 gene expression will enable us identify key steps in the regulatory pathway that may be explored as potential targets of therapeutic intervention in juvenile arthritis. Moreover, the proposed investigation into ways to inhibit PARP-1 activity in arthritis patients' blood cells may eventually help correct their IL-10 production deficit, thus restoring the patients' own immune capacity to control arthritic inflammation.