ROLE OF TISSUE-SPECIFIC STAT PROTEINS IN TUMOR AND AUTOIMMUNITY

Abstract

The signal transducer and activator of transcription (STAT) proteins transmit extracellular signals such as cytokines, growth factors and hormones, and thus critically regulate a plethora of biological processes. This thesis explores the context-dependent roles of two STAT proteins (STAT3 and STAT5) in two kinds of diseases, cancer and autoimmunity. By using a knockout mouse strain in which STAT3 was specifically deleted in endothelial cells (ECs), we demonstrated that loss of STAT3 in ECs suppressed tumor development. Then, we performed mechanistic study and revealed the importance of EC-specific STAT3 in mediating tumor angiogenesis and suppressing antitumor immunity. We also explored T-cell-specific function of STAT5 in autoimmunity. Mechanistic study revealed that loss of STAT5 resulted in defective arthritogenic potential of CD4+ T cells, which was largely due to impaired GM-CSF production. Furthermore, with insufficient GM-CSF production, STAT5-deficient CD4+ T cells were attenuated in accumulating neutrophils and inducing effective synovitis.