Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia modulates apoptosis and impairs NK function

TNFα levels are elevated in the marrows of patients with myelodysplastic syndrome (MDS) and are associated with high rates of apoptosis, which contributes to hematopoietic failure. We observed that exposure of human marrow stroma cell lines HS5 and HS27a to TNFα increases levels of IL-32 mRNA. IL-32...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2008-02, Vol.105 (8), p.2865-2870
Main Authors: Marcondes, A. Mario, Mhyre, Andrew J, Stirewalt, Derek L, Kim, Soo-Hyun, Dinarello, Charles A, Deeg, H. Joachim
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis - immunology
Biological Sciences
Blood
Blood cells
Bone marrow
Bone Marrow Cells - metabolism
CD56 Antigen - immunology
Cell culture
Cell Line
Cell lines
Cells
Cytokines
Gene expression
Gene Expression Regulation - immunology
Humans
Interleukins - immunology
Interleukins - metabolism
Killer Cells, Natural - immunology
Leukemia
Leukemia, Myelomonocytic, Chronic - immunology
Messenger RNA
Myelodysplastic syndromes
Myelodysplastic Syndromes - immunology
Natural killer cells
RNA Interference
Tumor Necrosis Factor-alpha - metabolism
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Summary:TNFα levels are elevated in the marrows of patients with myelodysplastic syndrome (MDS) and are associated with high rates of apoptosis, which contributes to hematopoietic failure. We observed that exposure of human marrow stroma cell lines HS5 and HS27a to TNFα increases levels of IL-32 mRNA. IL-32, in turn, induces TNFα. Marrow stroma from patients with MDS expressed 14- to 17-fold higher levels of IL-32 mRNA than healthy controls. In contrast, cells from patients with chronic myelomonocytic leukemia (CMML) expressed only one tenth the level of IL-32 measured in healthy controls. Human KG1a leukemia cells underwent apoptosis when cocultured with HS5 stromal cells, but knockdown of IL-32 in the stromal cells by using siRNA abrogated apoptosis in the leukemia cells. IL-32 knockdown cells also showed dysregulation of VEGF and other cytokines. Furthermore, CD56⁺ natural killer cells from patients with MDS and CMML expressed IL-32 at lower levels than controls and exhibited reduced cytotoxic activity, which was unaffected by IL-2 treatment. We propose that IL-32 is a marrow stromal marker that distinguishes patients with MDS and CMML. Furthermore, IL-32 appears to contribute to the pathophysiology of MDS and may be a therapeutic target.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0712391105