Fumaric acids as a novel antagonist of TLR-4 pathway mitigates arsenic-exposed inflammation in human monocyte-derived dendritic cells

Abstract

Exposure to environmentally relevant doses of arsenic has several harmful effects on the human immune system. In traditional Eastern medicines, nettle has been used as an anti-inflammatory agent to treat rheumatism and osteoarthritis. Fumaric acid (FA) as a major effective compound in nettle was chosen based on very accurate virtual screening to find antagonist for TLR4/MD structure. In this study, the in vitro therapeutic effects of FA on arsenic-exposed monocytes-derived dendritic cells (MDDCs) were evaluated. All the canonical functions of dendritic cells in bridging innate and adaptive immune system including phagocytosis and antigen-presenting capacity, and also cytokines secretion, were evaluated after exposure to arsenic/FA. FA profoundly over-expressed antigen-presenting capacity of MDDCs after exposure to arsenic through the upregulation of MHCιι. However, phagocytosis capacity of arsenic-exposed MDDCs is not compensated for, by treatment with FA. Arsenic up-regulates pro-inflammatory cytokines independents of TLR4 pathway. FA surprisingly mitigates the up-regulation of IL-1β and TNF-α but not TLR4 and NF-kB. Moreover, FA increases the viability of MDDCs even at a high dose of arsenic. Totally, FA reduced inflammatory factors induced by arsenic. This finding confirmed that nettle and other medicinal plants containing similar structures with FA could be further analyzed as valuable candidates for the reduction of drastic effects of arsenic in human immune systems.