This proposal is aimed at understanding the function of a recently discovered interleukin-1 (IL-4) induced gene, Figl. Because its expression is regulated by IL-4 and it is only expressed in lymphoid organs, we are particularly interested in understanding its role in immune function. The Figl protein is most similar to the L-amino acid oxidase (LAO) flavoenzyme found in snake venom. Interestingly, LAO kills cells by apoptosis through the production of hydrogen peroxide. Because Figl contains a hydrophobic leader peptide, we propose that Figl is secreted by cells to induce apoptosis of themselves or adjacent cells and thus regulating the immune response. We plan to test this by isolation nd purification of adjacent cells and thus regulating the immune response. We plan to test this by isolation and purification of Figl protein followed by determination if it has similar biochemical properties as LAO. We also plan to heavily explore the role of Figl in the immune system. Besides determination of the ability of Figl protein to induce apoptosis in immune cells, we plan to examine its ability to induce or modify other IL-4 mediated events, especially changes in cell surface protein expression. In addition, we plan to further characterize the expression pattern of Figl in immune cells and confirm whether or not it is a secreted protein. Figl genetically maps to the same region as Sle3, a systemic lupus erythematosus (SLE) susceptibility locus found in mice. Interestingly, some of the characteristics of Sle3 suggest that it may be Figl. Mice with Sle3 have high levels of polyreactive IgM and IgG and a expansion of CD4 T cells. One possible explanation for this phenotype, based on the predicted features of Figl protein, is that mutant Figl protein may not induce apoptosis in activated B cells or in CD4 T cells, resulting in elevated IgM and IgG and an increase in the CD4 T cells. We plan to determine if Figl and Sle3 are identical by genetic mapping in mice and attempting to recreate the Sle3 phenotype by introducing the affected allele into healthy mice. In addition, we plan to extend these studies to human SLE. If we discover that particular Figl polymorphisms are associated with human SLE, we may be closer to understanding some of the genetic basis for susceptibility to SLE. These proposed studies will not only provide new knowledge into the function of a previously uncharacterized protein, Figl, but may also provide exiting new insights into susceptibility to SLE, basic understanding of the development of autoimmunity, and regulation of the immune system.
| Mason, James M; Naidu, Mamta D; Barcia, Michele et al. (2004) IL-4-induced gene-1 is a leukocyte L-amino acid oxidase with an unusual acidic pH preference and lysosomal localization. J Immunol 173:4561-7 |
| Chavan, Sangeeta S; Tian, Wenzhi; Hsueh, Kevin et al. (2002) Characterization of the human homolog of the IL-4 induced gene-1 (Fig1). Biochim Biophys Acta 1576:70-80 |
| Tian, Wenzhi; Chua, Kevin; Strober, Warren et al. (2002) ILG1 : a new integrase-like gene that is a marker of bacterial contamination by the laboratory Escherichia coli strain TOP10F'. Mol Med 8:405-16 |
