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

Abstract

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.

Genetic variation in Interleukin-32 influence the immune response against New World Leishmania species and susceptibility to American Tegumentary Leishmaniasis

“…Although IL-32β is known to present proinflammatory properties [43], it has been shown that IL-32β induces IL-10 production [62]. IL-32α is regarded as anti-inflammatory member of the IL-32 family which is able to inhibit NK cell activation and JAK/STAT pathway [63]. Thus, in our study all three isoforms are associated with proinflammatory cytokines in ATL, it is possible that IL-32β and IL-32α act as anti-inflammatory mediators in the lesions, being important to decrease the inflammatory process, however, whether IL-32β or IL-32α acts as an anti-inflammatory mediators in lesions of ATL patients is not known at this moment.…”

Interleukin-32 promotes detachment and activation of human Langerhans cells in a human skin explant model

“…We showed that IL‐32‐specific siRNA in KCs strongly inhibited IL‐32 expression and consequently LC activation. While our manuscript was under review, Gorvel et al . showed that LCs expressed IL‐32 while in a ‘steady state’.…”

“…However, the method they used for LC isolation is quite different from ours. Gorvel et al . isolated LCs following 48 h of migration outside the skin, in contrast to the enzymatic digestion of skin cells used in our model.…”

“…However, the method they used for LC isolation is quite different from ours. Gorvel et al 27 isolated LCs following 48 h of migration outside the skin, in contrast to the enzymatic digestion of skin cells used in our model. Their method allows LC migration from the skin, which is often associated with activation and the IL-32 release can be observed.…”

The Biology and Role of Interleukin-32 in Tuberculosis

“…The IL-32 mRNA is highly expressed in immune cells, and IL-32 expression has also been detected in nonimmune tissues and cells [ 6 , 55 , 62 ]. NK cells [ 2 , 3 , 63 ], monocytes/macrophages [ 3 , 62 , 64 ], dendritic cells (DCs) from PBMCs [ 58 , 62 , 65 ], neutrophils [ 66 ], T lymphocytes [ 62 ], epithelial cells [ 67 ], endothelial cells [ 68 ], fibroblasts [ 69 ], and hepatocytes [ 64 ] can express IL-32. IL-32 is also expressed and released in both cancer and noncancer cell lines, including the HepG2 human cancer cell line [ 3 , 70 ], A549 cells [ 71 , 72 ], pancreatic cancer cell lines such as MIA PaCa-2, PANC-1, and BxPC-3 [ 73 , 74 ], the human hepatoma cell line Huh-7.5 [ 64 ], cervical cancer cells and tissues [ 75 ], the HEK293T cell line [ 34 , 57 ], the HT-29 human colon cell line [ 60 ], the human colon neuroendocrine LCC-18 cell line [ 34 ], human colonic subepithelial myofibroblasts [ 51 ], human primary keratinocytes [ 50 ], synovial cells and fibroblast-like synoviocytes (FLS) [ 14 , 69 ], and the marrow stromal cell lines HS-5 and HS-27A [ 76 ].…”