Vasculitis Foundation funds Dr. Liu’s study:
PARP-1 in CSS-associated IL-10 Promoter Polymorphisms
Churg-Strauss Syndrome (CSS) is a rare disorder associated with increased number of eosinophils in the blood, extravascular granulomas, and system small vessel vasculitis. The cause of CSS is unknown but is probably multi-factorial involved and genetic components may contribute to its development. The genetic component of CSS is complex, involving the effects of multiple genes at various points in the disease pathology, including tumor-necrosis factor-a (TNF-a) and several proteins secreted by immune cells (such as interleukin-2, 5 and interleukin-10 cytokines). Interleukin-10 is a protein produced by several types of immune cells including macrophages and lymphocytes, and acts mainly as an anti-inflammatory cytokine by inhibiting the production of proinflammatory cytokines, and antagonizing the effects of proinflammatory cytokines such as TNF-a. IL-10 is important in controlling the development of arthritis and lupus. It was found that the -3575T/-819A/-592C (TAC) genotype is associated with higher IL-10 production and more severe vasculitis than other genotypes in CSS patients, suggesting a high level of IL-10 may led to more severe disease in certain CSS patients.
To find a way to control overproduction of IL-10, we recently identified poly(ADP-ribose) polymerase 1 (PARP-1) as a nuclear protein able to repress IL-10 gene expression by differentially binding to the GCC haplotype of human IL-10 promoter in macrophages. PARP-1 is a highly conserved nuclear zinc-finger protein involved in maintenance of genomic integrity. Over-expression of PARP-1 led to less IL-10 production in the GCC type IL-10 promoter. We hypothesize that the overproduction of IL-10 in certain CSS patients with the TAC haplotype IL-10 promoter is due to its weaker ability to interact with the nuclear repressor PARP-1, resulting in higher IL-10 production in a chronic manner, which, in combination with other factors, promotes uncontrolled inflammation and pathology characteristic of CSS.
In this project, we will (1) investigate the molecular mechanisms by which PARP-1 mediates IL-10 gene expression; and (2) assess PARP-1 expression and enzyme activity in CSS patients.
The study will elucidate molecular mechanisms of the genetic variants important for the pathogenesis of CSS. It may also lead to identification of the PARP-1 as a new biomarker and a potential therapeutic target for CSS treatment.
For the proposed study, we may need extra CSS patients to participate in the study by providing about 4 teaspoons of blood. We hope that this study will provide us a better understanding of genetic basis of the disease and find a potential way to correct their immune disorders in future treatments.
If you are interested in participating in this study, please contact Dr. Terry Moore, 1402 South Grand Blvd., Doisy Hall 213A, St. Louis, MO 63104. Tel: 314-977-6195 or Dr. Jianguo Liu for detailed information.
Jianguo Liu, M.D., Ph.D.
Division of Immunobiology
Department of Internal Medicine
Saint Louis University School of Medicine
Doisy Research Center, Rm 811
1100 S. Grand Blvd.
St. Louis, MO 63104
Tel: 314-977-7533 (office)