Melatonin suppresses nitric oxide production in glial cultures by pro-inflammatory cytokines through p38 MAPK inhibition

Abstract

Melatonin has been shown to down-regulate inflammatory responses and provide neuroprotection. However, the mechanisms underlying the anti-inflammatory properties of melatonin are poorly understood. In the present work, we studied the modulatory effect of melatonin against pro-inflammatory cytokines in glial cell cultures. Treatment with pro-inflammatory cytokines mainly tumor necrosis factor-alpha, interleukin 1-beta, and interferon-gamma induces an increase in inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production. Pre-treatment with melatonin produced an inhibitory effect on iNOS expression and NO production. The biochemical studies revealed that cytokine treatment favors the activation of several pathways, such as mitogen-activated protein kinases (MAPKs), STAT1, and STAT3; however, the anti-inflammatory effect of melatonin was accompanied only by a decrease in p38 MAPK activity. Likewise, SB203580 a p38 kinase inhibitor inhibits NO production. These data indicate that the anti-inflammatory action of melatonin in glial cells after stimulation with pro-inflammatory cytokines may be in part, attributable to p38 inhibition which down-regulates iNOS expression and NO production.

Keywords::

• melatonin
• nitric oxide
• glial cells
• inflammation

Acknowledgments

We thank the Language Advisory Service of the University of Barcelona for revising this manuscript.

Declaration of interest

The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.

This study was funded by grant 2009/SGR00853 from the Generalitat de Catalunya (autonomous government of Catalonia), by grants BFU2010-19119/BFI, SAF2011-23631 and SAF2012-39852-C02-01 from the Spanish Ministerio de Ciencia e Innovación.