Curine Inhibits Macrophage Activation and Neutrophil Recruitment in a Mouse Model of Lipopolysaccharide-Induced Inflammation.

Jaime Ribeiro-Filho,Fagner Carvalho Leite,Alan De Brito Carneiro,Márcia Regina Piuvezam,Juliana Alves Azeredo,Edson Fernandes De Assis,Celidarque Da Silva Dias,Andrea Surrage Calheiros,Patrícia T Bozza

doi:10.3390/toxins11120705

Jaime Ribeiro-Filho, Fagner Carvalho Leite + Show 7 more

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https://doi.org/10.3390/toxins11120705

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Journal: Toxins	Publication Date: Dec 3, 2019
Citations: 8	License type: CC BY 4.0

Affiliation: Fundação Oswaldo Cruz, Universidade Federal da Paraíba

Abstract

Curine is a bisbenzylisoquinoline alkaloid (BBA) with anti-allergic, analgesic, and anti-inflammatory properties. Previous studies have demonstrated that this alkaloid is orally active at non-toxic doses. However, the mechanisms underlying its anti-inflammatory effects remain to be elucidated. This work aimed to investigate the effects of curine on macrophage activation and neutrophil recruitment. Using a murine model of lipopolysaccharide (LPS)-induced pleurisy, we demonstrated that curine significantly inhibited the recruitment of neutrophils in association with the inhibition of cytokines tumor necrosis factor (TNF-α), interleukin (IL)-1β, IL-6, monocyte chemotactic protein (CCL2/MCP-1) as well as leukotriene B4 in the pleural lavage of mice. Curine treatment reduced cytokine levels and the expression of iNOS in in vitro cultures of macrophages stimulated with LPS. Treatment with a calcium channel blocker resulted in comparable inhibition of TNF-α and IL-1β production, as well as iNOS expression by macrophages, suggesting that the anti-inflammatory effects of curine may be related to the inhibition of calcium-dependent mechanisms involved in macrophage activation. In conclusion, curine presented anti-inflammatory effects that are associated with inhibition of macrophage activation and neutrophil recruitment by inhibiting the production of inflammatory cytokines, LTB4 and nitric oxide (NO), and possibly by negatively modulating Ca2+ influx.

Highlights

Macrophages work as detectors of inflammatory signals, including those produced by the host and the derived from microorganisms, such as lipopolysaccharide (LPS) [1]
(2.5 mg/kg) or dexamethasone (2 mg/kg) 1 h prior to the LPS challenge caused a significant reduction in neutrophil counts (Figure 1B) in comparison with the group of untreated and challenged mice, demonstrating the inhibitory role played by curine with regard to neutrophil recruitment during the pleural inflammation
While LPS stimulation was found to induce increased expression of iNOS by macrophages, treatment with curine or verapamil reduced the expression of this enzyme (Figure 5B). These findings suggest that the inhibition of nitric oxide (NO) production through the curine-mediated regulation of iNOS expression could be associated with calcium influx inhibition

Summary

Introduction

Macrophages work as detectors of inflammatory signals, including those produced by the host and the derived from microorganisms, such as lipopolysaccharide (LPS) [1]. TLR4 induces macrophage activation by regulating intracellular pathways involved in cytokine, Toxins 2019, 11, 705; doi:10.3390/toxins11120705 www.mdpi.com/journal/toxins. Toxins 2019, 11, 705 lipid mediator and oxygen reactive species (ROS) production, in a process regulated by calcium signaling [2,3]. The mediators released by activated macrophages play critical roles in neutrophil recruitment and activation, and influence the progress of immune responses as well as the development of many inflammatory diseases [4,5]. Studies have shown that BBA are bioactive natural compounds presenting anti-inflammatory, anti-allergic, and analgesic activities [8] and there is evidence that their mechanism of action involves a direct inhibition of calcium channels [6,9,10]

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