Altered FOXO1 Transcript Levels in Peripheral Blood Mononuclear Cells of Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients

JNK-dependent downregulation of FoxO1 is required to promote the survival of fibroblast-like synoviocytes in rheumatoid arthritis

“…A study demonstrating selective reduction of FoxO1 levels in RA PBMCs suggested that alterations in FoxO1 expression might be involved in RA pathology 18. Here, we compared peripheral blood FoxO1 and FoxO3a mRNA expression in 10 methotrexate-naive RA patients and 15 healthy donors (HDs) previously subjected to global gene expression profiling 23.…”

“…Genes involved in cellular inflammatory responses are also direct FoxO targets,8 and studies in animals lacking FoxO proteins have provided evidence for essential roles of FoxO transcriptional activity in the immune system 33. In RA, reduced expression and PKB-mediated inactivation of FoxO family members has been reported,17 18 and SLE FoxO1 expression in PBMCs correlates negatively with disease severity,18 indicating FoxO involvement in protection against autoimmune processes. Here, we show that both peripheral and synovial FoxO1 expression are strongly associated with pathology in RA, as synovial FoxO1 expression correlates negatively with clinical parameters of disease activity and local IL-6 expression.…”

“…PKB-inactivated FoxO proteins are detected in RA synovial tissue, and synovial macrophages express elevated levels of inactive FoxO4 compared with disease controls 17. Peripheral blood mononuclear cells (PBMCs) of patients with RA express lower levels of FoxO1 than healthy individuals,18 and hypermethylation of the FoxO1 gene has been reported in RA FLS 19. In another IMID, reduced FoxO4 expression has been reported in colonic epithelial cells of patients with inflammatory bowel disease compared with healthy controls 20.…”

Epigenetic Regulation of B Lymphocyte Development and Repertoire Selection: Relevance to Autoimmunity

“…Several observations point to the existence of altered transcriptional regulation in SLE lymphocytes, with increased levels and types of defective transcripts relative to normal individuals, an abnormality that could alter functions of their lymphocytes [55][56][57]. Thus, studies of forkhead transcription factors (FOXO) that regulate cell proliferation and activation, cell survival and B cell class-switch recombination revealed that FOXO1 transcript levels are decreased in SLE patients with active disease activity [56], suggesting that deregulation in gene expression may be connected to the development of tissue damage mediated by the over-activation of autoreactive B lymphocytes.…”

“…Thus, studies of forkhead transcription factors (FOXO) that regulate cell proliferation and activation, cell survival and B cell class-switch recombination revealed that FOXO1 transcript levels are decreased in SLE patients with active disease activity [56], suggesting that deregulation in gene expression may be connected to the development of tissue damage mediated by the over-activation of autoreactive B lymphocytes.…”