Differential effects of TNF-α and IL-1β on the control of metal metabolism and cadmium-induced cell death in chronic inflammation.

Paola Bonaventura,Pierre Miossec,Aline Lamboux,Francis Albarède,Pierre Bobé

doi:10.1371/journal.pone.0196285

Abstract

ObjectiveInterleukin-1-beta (IL-1β) and tumour necrosis factor-alpha (TNF-α) are both monocyte-derived cytokines. Both cytokines have been previously described to exert a role in rheumatoid arthritis (RA) pathogenesis synergizing with other pro-inflammatory mediators, such as interleukin-17 (IL-17) on target cells, for the perpetuation of the inflammatory response (e.g. IL-6 production). In the context of experimental RA, Cd addition has an anti-proliferative and anti-inflammatory effect when associated to IL-17/TNF-α stimulation, due to its accumulation in synoviocytes. The aim of this work was to evaluate if IL-1β interaction with IL-17 also contributes to metal-import mechanisms and its effects on cell viability and inflammation.MethodsIL-17 and IL-1β were added to synoviocyte cultures with or without exogenous Cd addition (0.1 ppm, 0.89 μM). IL-6 production, Cd import kinetics, gene expression of ZIP-8 importer and metallothioneins (MTs) and cell viability were evaluated by ELISA, inductively-coupled mass spectrometry (ICP-MS), q-RT-PCR and viability assays (neutral red and annexin V) respectively.ResultsIL-17 and IL-1β acted in synergy on synoviocytes to induce IL-6 production similarly to the IL-17/TNF-α combination. Metal import was lower with IL17/ IL-1β in comparison to IL-17/TNF-α exposed-synoviocytes, as the expression of ZIP-8 and MT-1F was less induced. Monocyte and PBMCs exposure to Cd resulted in a reduced production of IL-1β and an increased production of TNF-α and this result was confirmed in co-cultures of synoviocytes and PBMCs. The IL-17/IL-1β combination with Cd slightly reduced cell viability in comparison to the IL-17/TNF-α combination and resulted in a strong induction of IL-6 production.ConclusionIL-17/TNF-α combination but not IL-17/IL-1β combination mainly drives the accumulation of Cd in synoviocytes and its effects on cell viability and inflammation.

Highlights

Interleukin-1-beta (IL-1β) and tumour necrosis factor alpha (TNF-α) are key cytokines produced by monocytes and activated macrophages
IL-17/TNF-α combination but not IL-17/IL-1β combination mainly drives the accumulation of Cd in synoviocytes and its effects on cell viability and inflammation
Low IL-1β concentration synergizes with IL-17 stimulating IL-6 production by synoviocytes to the IL-17 TNF combination

Summary

Introduction

Interleukin-1-beta (IL-1β) and tumour necrosis factor alpha (TNF-α) are key cytokines produced by monocytes and activated macrophages. IL-1β and TNF-α are both involved in a variety of cellular activities (cell proliferation, differentiation, and cell death) [2,3] but they differ for their structure, the cellular responses they induce and pathways of activation [4]. In various RA models, IL-1β and TNF-α mobilize and activate leukocytes, inducing B, T and natural killer cell proliferation [1]. Th17-cell produced IL-17, in turn, regulates IL-1β and TNF-α production [8,9] sometimes resulting in a synergistic interaction of IL-17 with one or both cytokines to increase the inflammatory response [10,11]

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