Interleukin-4 treatment reduces leukemia burden in acute myeloid leukemia

Interleukin-4 (IL-4) is a signature cytokine pivotal in Type 2 helper T cell (Th2) immune response, particularly in allergy and hypersensitivity. Interestingly, IL-4 increases endogenous levels of prostaglandin D-2 (PGD(2)) and its metabolites, Delta(12)-prostaglandin J(2) (Delta(12)-PGJ(2)) and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), collectively called cyclopentenone PGs (CyPGs). However, the therapeutic role of IL-4 in hematologic malignancies remains unclear. Here, we employed a murine model of acute myeloid leukemia (AML), where human MLL-AF9 fusion oncoprotein was expressed in hematopoietic progenitor cells, to test the effect of IL-4 treatment in vivo. Daily intraperitoneal treatment with IL-4 at 60 mu g/kg/d significantly alleviated the severity of AML, as seen by decreased leukemia-initiating cells (LICs). The effect of IL-4 was mediated, in part, by the enhanced expression of hematopoietic- PGD(2) synthase (H-PGDS) to effect endogenous production of CyPGs, through autocrine and paracrine signaling mechanisms. Similar results were seen with patient-derived AML cells cultured ex vivo with IL-4. Use of GW9662, a peroxisome proliferator-activated receptor gamma (PPAR gamma) antagonist, suggested endogenous CyPGs-PPAR gamma axis mediated p53-dependent apoptosis of LICs by IL-4. Taken together, our results reveal a beneficial role of IL-4 treatment in AML suggesting a potential therapeutic regimen worthy of clinical trials in patients with AML.

Automated summary

Interleukin-4 (IL-4) plays a therapeutic role in acute myeloid leukemia (AML) by alleviating the severity of the disease. IL-4 enhances the expression of hematopoietic- PGD(2) synthase (H-PGDS) to increase the production of endogenous cyclopentenone prostaglandins (CyPGs), leading to apoptosis of leukemia-initiating cells (LICs).