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

Beatrice Casu,Stefano Regis,Cristina Bottino,Andrea Petretto,Alessandra Dondero,Fabio Caliendo,Roberta Castriconi,Francesca Bellora,Martina Bartolucci

doi:10.3390/cancers11010075

Abstract

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.

Highlights

TGF-β1 is a pleiotropic factor secreted by several cell types in both homeostatic and pathological conditions [1,2]
IL-2 and IL-15 significantly contrasted the TGF-β1-mediated downregulation of the activating receptors, which recovered expression levels comparable to untreated Natural Killer (NK) cells
The present study describes an additive effect of IL-18 on some crucial regulatory functions of TGF-β1, strongly supporting the concept that IL-18 must be considered “more than a Th1 cytokine” [54]

Summary

Introduction

TGF-β1 is a pleiotropic factor secreted by several cell types in both homeostatic and pathological conditions [1,2]. It plays a crucial role in maintaining peripheral tolerance and regulating the magnitude of immune responses [3]. TGF-β1 is secreted in latent/inactive forms [1,3], non covalently associated with the latency-associated peptide (LAP) in small latency complexes (SLC) or, most commonly, in large latency complexes (LLC) consisting of SLC and the latent TGF-β1 binding protein (LTBP). Cancers 2019, 11, 75 physiological conditions large amounts of inactive TGF-β1 are present in body fluids and tissues that, where and when necessary, can be rapidly activated by different mechanisms. Additional modalities of TGF-β1 activation include the action of the membrane glycoprotein thrombospondin-1, shear stress, proteases, heat, acidic pH, and reactive oxygen species [3]

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Conclusion