- SLE is a multifactorial, heterogeneous disease, characterized by aberrant immune regulation, but the genetic traits conferring susceptibility and their interaction with environmental factors have not been elucidated yet. The long-term objectives of this proposal are to identify the factors predisposing to SLE. IL-6, a member of the cytokine network that regulates immune responses, is aberrantly expressed in SLE. Alleles of an AT-rich minisatellite in the IL-6 3' flanking region are associated with Caucasian and African-American SLE and with accumulation and stability of IL-6 mRNA. Thus, 3' alleles may affect IL-6 expression, and contribute to SLE pathogenesis.
The aims of this application are: (1) To confirm with higher level of significance the correlation of SLE-associated 3' alleles with upregulated IL-6, and to determine whether the SLE-associated 3' alleles constitute a basic trait that could delineate, along with other SLE factors, specific subsets of SLE; (2) to identify the molecular event(s) in IL-6 upregulation that are affected by the 3' alleles and the 3' sequences having gene regulatory potential; (3) to evaluate the possible association of IL-6 promoter alleles with SLE and differential IL-6 biology and, (4) to identify the DNA allelic sequences that contribute to IL-6 gene deregulation in SLE, and their possible interactions with other factors by measuring mRNA levels and stability of transfectants of CAT constructs containing allelic 3' flanking sequences identified for gene-regulatory potential by EMSA and DNase footprinting. Study of interactions of the 3' flanking allelic sequences with the IL-6 3' UTR, with cytokines affecting IL-6 mRNA stability in SLE (i.e., TNFalpha and IL-10), and with IL-6 promoter or 5' UT sequences. These studies can elucidate the pathways leading to deregulated IL-6 production in SLE and, by identifying the relevant DNA sequences, can provide useful predictive tools and advance our search for targeted therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042520-05
Application #
2769602
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1993-09-30
Project End
2000-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Linker-Israeli, M; Wallace, D J; Prehn, J et al. (1999) Association of IL-6 gene alleles with systemic lupus erythematosus (SLE) and with elevated IL-6 expression. Genes Immun 1:45-52
Linker-Israeli, M; Wallace, D J; Prehn, J L et al. (1996) A greater variability in the 3' flanking region of the IL-6 gene in patients with systemic lupus erythematosus (SLE). Autoimmunity 23:199-209