TY - JOUR
T1 - Novel Immunoregulatory Functions of IL-18, an Accomplice of TGF-β1
AU - Casu, Beatrice
AU - Dondero, Alessandra
AU - Regis, Stefano
AU - Caliendo, Fabio
AU - Petretto, Andrea
AU - Bartolucci, Martina
AU - Bellora, Francesca
AU - Bottino, Cristina
AU - Castriconi, Roberta
PY - 2019/1/11
Y1 - 2019/1/11
N2 - 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.
AB - 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.
U2 - 10.3390/cancers11010075
DO - 10.3390/cancers11010075
M3 - Article
C2 - 30641867
VL - 11
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 1
ER -