Interrogating the Mechanistic Basis for Cytokine-Mediated Glucocorticoid Resistance in Lymphoid-Driven Diseases
- Author(s): Meyer, Lauren Kimberly
- Advisor(s): Hermiston, Michelle
- Shannon, Kevin
- et al.
Glucocorticoids (GCs) are potently immunosuppressive due to their pro-apoptotic effects on lymphoid cells, leading to their utility in a wide range of clinical contexts including autoimmune diseases, hyperinflammatory conditions, and lymphoid malignancies. In addition, GCs are endogenously produced hormones that mediate a wide range of physiologic functions that are essential for life. As a result, cells of the immune system face constant exposure to GCs and therefore require intrinsic mechanisms by which to resist their pro-apoptotic effects under certain developmental and environmental conditions. The retention of these resistance mechanisms in lymphoid-driven diseases thereby poses a challenge to the clinical use of GCs in these contexts. Common -chain cytokines, through activation of the JAK/STAT signal transduction pathway, play essential roles in the differentiation, survival, and function of lymphoid cells. Here, we assess the interplay between GC activity and cytokine-mediated pro-survival signaling in two lymphoid-driven diseases, acute lymphoblastic leukemia and hemophagocytic lymphohistiocytosis, and demonstrate that cytokines are potent mediators of GC resistance. Mechanistically, we show that activation of STAT5 downstream of cytokine receptor signaling is necessary for cytokine-induced GC resistance. STAT5 functions as a transcription factor to upregulate expression of anti-apoptotic mediators, thereby reducing the apoptotic potential and promoting the survival of lymphoid cells. Through both genetic and pharmacologic approaches, we demonstrate that targeted inhibition of cytokine receptor signaling effectively restores GC sensitivity, and we establish the feasibility of this therapeutic approach in two in vivo models of disease.