Antimalarial drugs inhibit IFNα-enhanced TNFα and STAT4 expression in monocytes: Implication for systemic lupus erythematosus

Patricia López,Javier Rodríguez-Carrio,Ana Suárez

doi:10.1016/j.cyto.2014.02.002

Patricia López, Javier Rodríguez-Carrio + Show 1 more

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https://doi.org/10.1016/j.cyto.2014.02.002

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Journal: Cytokine	Publication Date: Feb 26, 2014
Citations: 9	License type: cc-by

Affiliation: University of Oviedo

Abstract

ObjectivesTo analyse the influence of IFNα on TNFα production by human peripheral blood mononuclear cells (PBMCs), as well as the possible interference of this cytokine on the effect of antimalarial drugs, TNFα regulators widely used in the treatment of systemic lupus erythematosus (SLE). MethodsPBMCs, monocytes or T cells were treated with IFNα alone or simultaneously to cellular stimuli as well as in the presence or absence of chloroquine. Supernatants from such cultures were collected to quantify TNFα by ELISA. TNFα and STAT4 expression in cultured cells were analysed by intracellular flow cytometry. In addition, STAT4 gene expression and serum levels of TNFα and IFNα were quantified in 53 SLE patients and 45 controls. ResultsIFNα alone did not modify significantly TNFα production, but an increase was observed in stimulated PBMC. Further analyses showed that monocytes were the cellular population responsible for this effect. In addition, IFNα treatment increased STAT4 in stimulated monocytes, suggesting that TNFα upregulation could be mediated by STAT4. On the other hand, the analysis of the antimalarial effect showed that chloroquine was able to inhibit in vitro the expression of TNFα and STAT4 enhanced by IFNα. In antimalarial-treated SLE patients, however, only those with high IFNα serum levels presented lower expression of STAT4. ConclusionsIFNα treatment enhances the induction of TNFα and STAT4 in stimulated monocytes, an effect inhibited in vitro by chloroquine treatment. However, the consequence of antimalarial treatment on SLE patients could be different depending on their IFNα serum levels.

Highlights

Interferon alpha (IFNa) is a cytokine of the type I IFN family with a wide range of effects upon the immune system, including a potent host-protective antiviral response
It is well known that antimalarial therapy inhibits the production of TNFa and other proinflammatory cytokines [20,21], we wanted to determine the influence of these drugs on the production of TNFa induced by IFNa
signal transducer and activator of transcription 4 (STAT4) enhanced by IFNa, in an attempt to evaluate this effect in vivo, we studied STAT4 gene expression and TNFa serum levels in 53 systemic lupus erythematosus (SLE) patients with (n = 29) and without (n = 24) antimalarial therapy and presenting different IFNa serum levels

Summary

Introduction

Interferon alpha (IFNa) is a cytokine of the type I IFN family with a wide range of effects upon the immune system, including a potent host-protective antiviral response. IFNa can induce the activation, differentiation and maturation of monocytes into dendritic cells (DCs), increasing the expression of MHC and co-stimulatory molecules [1,2]. It can produce B cell activation, differentiation and antibody production [3]. These immune-stimulant functions place IFNa in a critical position bridging innate and adaptive immune responses, and suggest that. IFNa could be important in the pathogenesis of autoimmunity.

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