A role for STAT5 in steroid-resistant UC?

To the Editor: Glucocorticoids (GCs) are powerful immunosuppressive agents that form the basis of current ulcerative colitis (UC) therapy. However, GC resistance has been reported in up to 30% of UC patients, thereby significantly complicating the clinical management of UC. Delineation of the molecular basis responsible for GC resistance is vital for the development of new therapeutic options in UC and may provide novel insights into the underlying proinflammatory mechanisms. A physical and functional interaction between the GC receptor and signal transducers and activators of transcription 5 (STAT5) has been demonstrated. Goleva et al reported a defect in GC receptor nuclear translocation in response to GCs because of phosphorylated STAT5-GC receptor heterodimer formation, resulting in GC insensitivity. This observation supported previous work demonstrating STAT5-dependent inhibition of GC-induced transcriptional effects through direct protein interaction. The STAT family consists of 7 STAT members (1, 2, 3, 4, 5A, 5B, and 6) that play an important role in inflammatory responses. STAT proteins are cytoplasmic transcription factors that become phosphorylated upon signaling by extracellular cytokines, after which dimerization and nuclear translocation takes place, thereby regulating transcriptional processes. The clinical importance of GC resistance combinedwith the abovementioned considerations prompted us to investigate the role of STAT5 in GCresistant UC. Colon biopsies from GC-resistant (n = 5) and non-GC-resistant UC (n = 4) patients were analyzed with immunohistochemistry. Biopsies from patients who underwent colonoscopy for colon cancer screening (n = 5) served as a control. These studies revealed the presence of phosphorylated (i.e., active) STAT5 in colon biopsies of GC-resistant UC patients, which was localized to intestinal epithelial cells and lamina propria mononuclear cells (LPMCs). In contrast, almost no phosphorylated STAT5 was observed in biopsies obtained from nonGC-resistant UC patients, and phosphorylated STAT5 was undetectable in biopsies from control (i.e., non-UC) patients. In addition, tissue lysates prepared from colon biopsies obtained from GC-resistant UC patients (n = 4) were subjected to immunoprecipitation using an antibody against the GC receptor. GC receptor immunoprecipitates were subsequently analyzed on Western blot, revealing the presence of phosphorylated STAT5. Thus, these observations showed an in vivo interaction between the GC receptor and phosphorylated STAT5 in steroid-resistant UC. Overall, this work suggests that STAT5 is involved in GCresistant UC and identifies LPMCs and intestinal epithelial cells as target cells for GC therapy in this disease. Previous studies revealed a potential role for STAT1, STAT3, and STAT4 in experimental colitis. Correspondingly, increased amounts of total and phosphorylated STAT3 were detected in LPMCs from UC and Crohn_s disease patients compared with noninflammatory control cells, as assessed by flow cytometry and immunohistochemistry. However, there were no data available on STAT5 in UC. Our findings now suggest that a subgroup of the UC population (i.e., GC-resistant UC patients) have increased phosphorylated STAT5 levels in the colon. Therefore, this study identifies STAT5 as a potential molecular target for the clinical management of GCresistant UC. Further studies will need to define the exact role of STAT5 in the pathogenesis of GC-resistant UC.