IL-32θ gene expression in acute myeloid leukemia suppresses TNF-α production

• Published in: Oncotarget 2015-12, Vol.6 (38), p.40747-40761
• Main Authors: Kim, Man Sub, Kang, Jeong-Woo, Jeon, Jae-Sik, Kim, Jae Kyung, Kim, Jong Wan, Hong, Jintae, Yoon, Do-Young
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Blotting, Western; Case-Control Studies; Chromatin Immunoprecipitation; Female; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Interleukin-6 - genetics; Interleukin-6 - metabolism; Interleukins - genetics; Interleukins - metabolism; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Male; Middle Aged; NF-kappa B - genetics; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Real-Time Polymerase Chain Reaction; Research Paper; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Young Adult
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5688

The proinflammatory cytokine TNF-α is highly expressed in patients with acute myeloid leukemia (AML) and has been demonstrated to induce rapid proliferation of leukemic blasts. Thus suppressing the production of TNF-α is important because TNF-α can auto-regulate own expression through activation of NF-κB and p38 mitogen-activated protein kinase (MAPK). In this study, we focused on the inhibitory effect of IL-32θ on TNF-α production in acute myeloid leukemia. Approximately 38% of patients with AML express endogenous IL-32θ, which is not expressed in healthy individuals. Furthermore, plasma samples were classified into groups with or without IL-32θ; then, we measured proinflammatory cytokine TNF-α, IL-1β, and IL-6 levels. TNF-α production was not increased in patients with IL-32θ expression than that in the no-IL-32θ group. Using an IL-32θ stable expression system in leukemia cell lines, we found that IL-32θ attenuated phorbol 12-myristate 13-acetate (PMA)-induced TNF-α production. IL-32θ inhibited phosphorylation of p38 MAPK, inhibitor of κB (IκB), and nuclear factor κB (NF-κB), which are key positive regulators of TNF-α expression, and inhibited nuclear translocation of NF-κB. Moreover, the presence of IL-32θ attenuated TNF-α promoter activity and the binding of NF-κB with the TNF-α promoter. In addition, IL-32γ-induced TNF-α production has no correlation with inhibition of TNF-α via IL-32θ expression. Thus, IL-32θ may serve as a potent inhibitor of TNF-α in patients with AML.