Project description:The present study demonstrated that pim1-promoted mito-Ca2+ influx enhanced the activity of mitochondrial OXPHOS, bringing about the differentiation of Th17 and driving the pathogenic progression of inflammatory arthritis. Targeting pim1 impeded Th17 differentiation and alleviated collagen-induced arthritis (CIA) and SKG arthritis, suggesting that Pim1 is a target for the treatment of inflammatory arthritis.
Project description:The Ras family of GTPases play an important role in signaling nodes downstream to T cell receptor and CD28 activation, potentially lowering the threshold for TCR activation by autoantigens. Somatic mutation in NRAS or KRAS may cause a rare autoimmune disorder coupled with abnormal expansion of lymphocytes. T cells from Rheumatoid Arthritis (RA) patients show excessive activation of Ras/MEK/ERK pathway. The small molecule farnesylthiosalicylic acid (FTS) interferes with the interaction between Ras GTPases and their prenyl-binding chaperones to inhibit proper plasma membrane localization. In the present study, we tested the therapeutic and immunomodulatory effects of FTS and its derivative 5-fluoro-FTS (F-FTS) in the rat adjuvant-induced arthritis model (AIA). We show that AIA severity was significantly reduced by oral FTS and F-FTS treatment compared to vehicle control treatment. FTS was as effective as the mainstay anti-rheumatic drug methotrexate, and combining the two drugs significantly increased efficacy compared to each drug alone. We also discovered that FTS therapy inhibited both the CFA-driven in vivo induction of Th17 and IL-17/IFN-g producing double positive as well as the upregulation of serum levels of the Th17-associated cytokines IL-17A and IL-22. By gene microarray analysis of effector CD4+ T cells from CFA-immunized rats, re-stimulated in vitro with the mycobacterium tuberculosis heat-shock protein 65 (Bhsp65), we determined that FTS abrogated the Bhsp65-induced transcription of a large list of genes (e.g. Il17a/f, Il22, Ifng, Csf2, Lta, and Il1a). The functional enrichment bioinformatics analysis showed significant overlap with predefined gene sets related to inflammation, immune system processes and autoimmunity. In Conclusions, FTS and F-FTS display broad immunomodulatory effects in AIA with inhibition of the Th17-type response to a dominant arthritogenic antigen. Hence, targeting Ras signal-transduction cascade is a potential novel therapeutic approach for RA.
Project description:Chronic inflammation is responsible for a number of debilitating human diseases including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. The Th17 subset of T lymphocytes is an important player in the development of these pathogenic conditions. The transcription factor, RORgt was initially coined the master regulator of the Th17 program, but targeting RORgt therapeutically is dangerous owing to an enhanced risk of thymoma upon its inhibition. Another ROR family member, RORa, has also been implicated in Th17 function.
Project description:Chronic inflammation is responsible for a number of debilitating human diseases including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. The Th17 subset of T lymphocytes is an important player in the development of these pathogenic conditions. The transcription factor, RORgt was initially coined the master regulator of the Th17 program, but targeting RORgt therapeutically is dangerous owing to an enhanced risk of thymoma upon its inhibition. Another ROR family member, RORa, has also been implicated in Th17 function.
Project description:Chronic inflammation is responsible for a number of debilitating human diseases including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. The Th17 subset of T lymphocytes is an important player in the development of these pathogenic conditions. The transcription factor, RORgt was initially coined the master regulator of the Th17 program, but targeting RORgt therapeutically is dangerous owing to an enhanced risk of thymoma upon its inhibition. Another ROR family member, RORa, has also been implicated in Th17 function.
Project description:Chronic inflammation is responsible for a number of debilitating human diseases including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. The Th17 subset of T lymphocytes is an important player in the development of these pathogenic conditions. The transcription factor, RORgt was initially coined the master regulator of the Th17 program, but targeting RORgt therapeutically is dangerous owing to an enhanced risk of thymoma upon its inhibition. Another ROR family member, RORa, has also been implicated in Th17 function.
Project description:Inflammation is a key component of pathological angiogenesis. Here we induce cornea neovascularisation using sutures placed into the cornea, and sutures are removed to induce a regression phase. We used whole transcriptome microarray to monitor gene expression profies of several genes