Altered TNF-α response by Aconibal® and methotrexate in a lipopolysaccharide-induced setting of inflammatory conditions: Potential on a synergistic combination

Abstract

Ethnopharmacological relevanceAconitum carmichaelii (AC) is a common herbal medicine used as anti-inflammatory and analgesic agent in Eastern Asia. In Korea, a commercial processed AC (Aconibal®) is traditionally used to treat the symptoms of spondylosis deformans and rheumatic pain. Aim of studyRheumatoid arthritis (RA) is systemic and autoimmune disease characterized by chronic inflammation. Methotrexate (MTX) is often the first-line therapy for RA. If MTX monotherapy is ineffective or RA is initially severe, adding a tumor necrosis factor alpha (TNF-α) inhibitor to the treatment can be beneficial. However, its inhibitory effects on RA when combined with MTX are unknown. Therefore, we investigated the stable modulation of and synergistic to additive effect on TNF-α using AC combined with MTX (AMC). Materials and methodsAn inflammatory response mimicking RA was induced in the mouse macrophage cell line Raw 264.7 using interferon-γ or lipopolysaccharide (LPS). We predicted that AC and MTX at a 3:1 ratio would have synergistic therapeutic effects and this was determined using the Chou-Talalay method of median effect analysis and CalcuSyn software. We analyzed the profiles of various inflammatory cytokine-related proteins using Search tool for retrieval of interacting genes and Kyoto Encyclopedia of Genes and Genomes. ResultsThe expression levels of selected inflammatory immune mediators such as interleukin (IL)-6, IL-1α, chemokine ligand 5, granulocyte-colony stimulating factor, nitric oxide synthase, and cyclooxygenase were reduced via regulation of the mitogen-activated protein kinase signaling pathway. AMC inhibited the levels of matrix metalloproteinases-1 and −3 in the human synovial cell line SW982. ConclusionsOur data show for the first time the potential beneficial effects of AMC in RA management.