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

Marcondes, A. Mario; Mhyre, Andrew J.; Stirewalt, Derek L.; Kim, Soo Hyun; Dinarello, Charles A.; Deeg, H. Joachim

doi:10.1073/pnas.0712391105

Cited by 121 publications

(111 citation statements)

References 35 publications

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“…Indeed, the control of NK cell activation and inhibition by and following IL-15 is critical. The absence of IL-15 or overexpression of IL-32a during infection or cancer might lead to progression or persistence of the disease due to the lack of NK cell killing (54)(55)(56). In contrast, an overexpression of IL-15 without proper regulation could cause autoimmunity (57) or even induce leukemia through DNA hypermethylation and chromosome instability (52).…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cell–Derived IL-32α: A Novel Inhibitory Cytokine of NK Cell Function

Gorvel

Korenfeld

Tung

et al. 2017

The Journal of Immunology

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Cytokines produced by dendritic cells (DCs) can largely determine the direction of immunity. Transcriptional analysis revealed that besides IL-15, IL-32 was the only other cytokine expressed by human Langerhans cells. IL-32 is a human cytokine that exists in four main isoforms. Currently, little is known about the regulation and function of the various IL-32 isoforms. In this study, we found that IL-15 is a potent inducer of IL-32α in DCs. Because IL-15 promotes NK cell activation, we investigated the interplay between IL-32 and IL-15 and their role in NK cell activity. We show that IL-32α acts on NK cells to inhibit IL-15–mediated STAT5 phosphorylation and to suppress their IL-15–induced effector molecule expression and cytolytic capacity. IL-32α also acted on DCs by downregulating IL-15–induced IL-18 production, an important cytokine in NK cell activity. Blocking IL-32α during DC:NK cell coculture enhanced NK cell effector molecule expression as well as their cytolytic capacity. Taken together, our findings suggest a feedback inhibition of IL-15–mediated NK cell activity by IL-32α.

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Section: Discussionmentioning

confidence: 99%

Dendritic Cell–Derived IL-32α: A Novel Inhibitory Cytokine of NK Cell Function

Gorvel

Korenfeld

Tung

et al. 2017

The Journal of Immunology

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“…IL-32 has also been shown to induce apoptosis in other experimental conditions. For example, Marcondes et al (46) showed that KG1a leukemic cells underwent apoptosis when cocultured with HS5 stromal cells and that apoptosis was due to IL-32 produced by the stromal cells. The abundant expression of IL-32 in lungs of COPD patients (66) may indirectly indicate increased apoptosis because apoptosis is considered to be an important mechanism in the pathogenesis of COPD.…”

Section: Discussionmentioning

confidence: 99%

“…Goda et al (51) showed that IL-32 induces apoptosis in T cells. More recently, IL-32 produced by stromal cells induced apoptosis of cocultured leukemic cells (46). Because apoptosis is an important effector mechanism for killing intracellular M. tuberculosis bacteria (62), we measured the effect of exogenous IL-32 on apoptosis of THP-1 cells.…”

Section: Il-32a or Il-32g Induces Macrophage Apoptosis In The Presencmentioning

confidence: 99%

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IL-32 Is a Host Protective Cytokine against Mycobacterium tuberculosis in Differentiated THP-1 Human Macrophages

Bai

Kim

Azam

et al. 2010

The Journal of Immunology

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132

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Macrophages provide a first line of defense against Mycobacterium tuberculosis. However, in instances where macrophage activation for killing is suboptimal, M. tuberculosis is capable of surviving intracellularly. IL-32 is a recently described cytokine induced by M. tuberculosis in a variety of cell types including human monocytes and macrophages. In this study, we investigated the biological significance of IL-32 in an in vitro model of M. tuberculosis infection in differentiated THP-1 human macrophages in which IL-32 expression was silenced using stable expression of short hairpin RNA (shRNA). Inhibition of endogenous IL-32 production in THP-1 cells that express one of three distinct shRNA-IL-32 constructs significantly decreased M. tuberculosis induction of TNF-α by ∼60%, IL-1β by 30–60%, and IL-8 by 40–50% and concomitantly increased the number of cell-associated M. tuberculosis bacteria compared with THP-1 cells stably expressing a scrambled shRNA. In THP-1 cells infected with M. tuberculosis and stimulated with rIL-32, a greater level of apoptosis was observed compared with that with M. tuberculosis infection alone. Obversely, there was significant abrogation of apoptosis induced by M. tuberculosis and a concomitant decrease in caspase-3 activation in cells depleted of endogenous IL-32. rIL-32γ significantly reduced the number of viable intracellular M. tuberculosis bacteria, which was modestly but significantly abrogated with a caspase-3 inhibitor. We conclude that IL-32 plays a host defense role against M. tuberculosis in differentiated THP-1 human macrophages.

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“…The exact function of IL-32 is not clear but it has been implicated in inflammatory disorders such as rheumatoid arthritis (14), Mycobacterium tuberculosis infection (15), and inflammatory bowel disease (16). Recently, there has been a focus on the expression of IL-32 in human malignancies such as stomach cancer (17), lung cancer (18), pancreatic cancer (19), hematopoietic malignancies (20,21), and uterine cervical cancer (22). There are no previous studies about the expression of IL-32 in RCC.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of IL-32 is a novel prognostic factor in patients with localized clear cell renal cell carcinoma

et al. 2011

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Abstract. ) is a proinflammatory cytokine that acts as a significant pathogenetic factor in various diseases and malignancies. However, the clinical effect of IL-32 expression in renal cell carcinoma (RCC) has not previously been investigated. The aim of the present study was to examine the significance of IL-32 overexpression in localized clear cell RCC (CCRCC). We examined 112 patients with localized CCRCC who underwent nephrectomy. The clinicopathological data were obtained by retrospective review and the expression levels of IL-32 were studied by immunohistochemistry. Tumors were classified according to staining intensity (0, no staining intensity; 1, weak; 2, intermediate; 3, strong). The cases with staining intensities from 0 to 2 comprised the IL-32 low-expression group (LEG), whereas those with a staining intensity of 3 comprised the IL-32 high-expression group (HEG). Correlations between IL-32 expression and clinicopathological parameters were determined. Staining intensities were determined for all cases as follows: 26 cases (23.2%) (score 0), 43 cases (38.4%) (score 1), 31 cases (27.7%) (score 2) and 12 cases (10.7%) (score 3). IL-32 HEG exhibited a higher recurrence rate compared to the IL-32 LEG (50 vs. 13%, P= 0.001). For survival rates, the 5-year recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) rates were lower in the IL-32 HEG group compared with the IL-32 LEG group (RFS, P= 0.001; DSS, P<0.001; OS, P= 0.026, respectively). Univariate analyses revealed that Fuhrman nuclear grade and a high IL-32 expression were significant prognostic factors for predicting RFS, DSS and OS in CCRCC, whereas multivariate analyses indicated that Fuhrman nuclear grade and high IL-32 expression were still independent risk factors. In conclusion, IL-32 overexpression was associated with high recurrence rates and low RFS, DSS and OS, indicating that it may be a novel prognostic factor for predicting outcomes in patients with CCRCC.

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

Cited by 121 publications

References 35 publications

Dendritic Cell–Derived IL-32α: A Novel Inhibitory Cytokine of NK Cell Function

Dendritic Cell–Derived IL-32α: A Novel Inhibitory Cytokine of NK Cell Function

IL-32 Is a Host Protective Cytokine against Mycobacterium tuberculosis in Differentiated THP-1 Human Macrophages

Overexpression of IL-32 is a novel prognostic factor in patients with localized clear cell renal cell carcinoma

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