Abstract
The inhibition of activated macrophages has been used to develop anti‐inflammatory agents for therapeutic intervention to human diseases that cause excessive inflammatory responses. Antofine, a phenanthroindolizidine alkaloid, has a potent anti‐inflammatory effect. However, the molecular mechanisms of its anti‐inflammatory activity have not yet been fully detailed. In this study, we comprehensively explored the anti‐inflammatory effects of antofine on endotoxin‐induced inflammation in macrophages using cDNA microarray analysis, thereby elucidating the potential mechanism by which antofine suppresses inflammation. Antofine significantly suppressed the secretion of proinflammatory cytokines such as TNF α and IL‐1β and the production of iNOS in LPS‐activated Raw264.7 macrophage cells. In addition, antofine can suppress the expressions of several inflammation‐related genes (such as ARG‐1, IL1F9, IL‐10, and IL‐33) and extracellular matrix genes (such as TNC and HYAL1), as well as a vasopressor gene (EDN1) in activated macrophage cells, that are induced by LPS stimulation. The gene expression profiles analyzed by GeneMANIA software showed that antofine not only contributed anti‐inflammatory activity but also modulated the cellular metabolism via AMPK. Furthermore, antofine also modulated the activation of AMPK and caspase‐1, the key regulator in inflammasome‐mediated IL‐1β maturation, in activated macrophage cells. In conclusion, these data indicated that antofine potentially can not only contribute an anti‐inflammatory effect but can also attenuate the metabolic disorders induced by inflammation via AMPK.
Highlights
Endotoxin-induced acute and excessive inflammatory responses in patients including endotoxemia and systemic inflammatory response syndrome (SIRS) still cause high mortality despite advanced supportive care and clinical therapeutic intervention (Cohen 2002)
A cell viability assay was performed to elucidate whether or not the suppressive effect on the production of inflammation-related genes was due to cell death, and the results showed that antofine exhibited no cell cytotoxicity in Raw264.7 macrophage cells at doses below 10 ng/mL but dramatically suppressed cell proliferation at a dose of 50 ng/mL (Fig. 1B)
These data indicated that antofine potentially can contribute an anti-inflammatory effect but can attenuate the metabolic disorders induced by inflammation via AMP-activated protein kinase (AMPK)
Summary
Endotoxin-induced acute and excessive inflammatory responses in patients including endotoxemia and systemic inflammatory response syndrome (SIRS) still cause high mortality despite advanced supportive care and clinical therapeutic intervention (Cohen 2002). Lipopolysaccharide (LPS), a bacterial endotoxin, can stimulate the acute a 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.
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