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Cancers 2019, 11(1), 75;

Novel Immunoregulatory Functions of IL-18, an Accomplice of TGF-β1

Dipartimento di Medicina Sperimentale, University of Genova, 16132 Genova, Italy
Istituto Giannina Gaslini, 16147 Genova, Italy
Centro di Eccellenza per la Ricerca Biomedica (CEBR), University of Genova, 16132 Genova, Italy
Author to whom correspondence should be addressed.
These authors contributed equally to this study.
Current address: Department of Biological Engineering, Synthetic Biology Center, Massachusetts Institute of Technology, 500 Technology Square, Cambridge, MA 02139, USA.
Received: 2 December 2018 / Revised: 27 December 2018 / Accepted: 4 January 2019 / Published: 11 January 2019
(This article belongs to the Special Issue Natural Killer Cells and Cancer Therapy)
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TGF-β1 is a pleiotropic factor exerting a strong regulatory role in several cell types, including immune cells. In NK cells it profoundly alters the surface expression of crucial activating and chemokine receptors. To understand which soluble signals might better contrast these effects, we cultured human NK cells in the presence of TGF-β1 and different innate and adaptive cytokines, generally referred as “immunostimulatory”. These included IL-2, IL-15, IL-21, IL-27, and IL-18. Unexpectedly, IL-18 strengthened rather than contrasting important TGF-β1-mediated functions. In particular, IL-18 further reduced the expression of CX3CR1 and NKp30, leading to the virtual abrogation of the triggering capability of this activating receptor. Moreover, IL-18 further increased the expression of CXCR4. The IL-18-mediated additive effect on NKp30 and CXCR4 expression involved transcriptional regulation and activation of MEK/ERK and/or p38MAPK. A proteomic approach quantified both surface and intracellular proteins significantly modified in cytokine-treated NK cells, thus giving global information on the biological processes involving TGF-β1 and IL-18. Our data support the concept that IL-18 may have a different behavior depending on the type of soluble factors characterizing the microenvironment. In a TGF-β1 rich milieu such as tumors, it may contribute to the impairment of both NK cells recruitment and killing capability. View Full-Text
Keywords: NK cells; TGF-β1; IL-18; cytokines; NKp30; activating receptors; CXCR4; chemokine receptors; p38MAPK; MEK/ERK NK cells; TGF-β1; IL-18; cytokines; NKp30; activating receptors; CXCR4; chemokine receptors; p38MAPK; MEK/ERK

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Casu, B.; Dondero, A.; Regis, S.; Caliendo, F.; Petretto, A.; Bartolucci, M.; Bellora, F.; Bottino, C.; Castriconi, R. Novel Immunoregulatory Functions of IL-18, an Accomplice of TGF-β1. Cancers 2019, 11, 75.

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