Autoimmune and inflammatory conditions such as rheumatoid arthritis are characterized by cellular infiltrates and the cytokines they secrete. The stimuli controlling cellular activation are received at the surface of inflammatory cells by receptors, transmitted by a signal transduction cascade to selected transcription factors, and result in modulation of gene transcription. The transcription factors that control the inflammatory response are therefore attractive candidates for therapeutic intervention in rheumatic diseases. The role of the transcription factor hXBP-1 (human X-box binding protein- 1) in inflammation has recently begun to emerge. hXBP-1 is strongly expressed in rheumatoid synovium, and in vitro studies suggest that hXBP-1 is involved in the control of MHC class II expression and in the B-lymphocyte differentiation pathway. However, the mechanism of action for hXBP-1 in these processes remains unknown. In order to gain a better understanding of the functions of hXBP-1, they have used gene targeting to generate mice deficient in hXBP-1 and have found an embryonic lethal phenotype. Therefore, they have additionally produced hXBP-1-deficient embryonic stem cells in order to generate hXBP-1-deficient/RAG-2-deficient chimeric mice for study of B- and T-lymphocytes lacking hXBP-1. They will use hXBP-1-deficient cells and cell lines to establish if hXBP-1 is phosphorylated upon activation, and to define the proinflammatory stimuli and cellular stressors that act on hXBP-1. The preferred target genes for hXBP-1 will be identified by using a modified subtractive hybridization strategy. This knowledge will be applied to the HTLV-1-transgenic mouse model of rheumatoid arthritis to assess if a dominant-negative mutant of hXBP-1 reduces joint inflammation.
