Abstract
Extracts from Taiwan’s traditional medicinal mushroom, Antrodia cinnamomea, exhibit anti-inflammatory activities in cellular and preclinical studies. However, this paper is the first to report that Antcin K, a triterpenoid isolated from A. cinnamomea, inhibits proinflammatory cytokine production in human rheumatoid synovial fibroblasts (RASFs), which are major players in rheumatoid arthritis (RA) disease. In our analysis of the mechanism of action, Antcin K inhibited the expression of three cytokines (tumor necrosis factor alpha [TNF-α], interleukin 1 beta [IL-1β] and IL-8) in human RASFs; cytokines that are crucial to RA synovial inflammation. Notably, incubation of RASFs with Antcin K reduced the phosphorylation of the focal adhesion kinase (FAK), phosphoinositide 3-kinase (PI3K), protein kinase B (AKT) and nuclear factor-κB (NF-κB) signaling cascades, all of which promote cytokine production in RA. Intraperitoneal injections of Antcin K (10 mg/kg or 30 mg/kg) attenuated paw swelling, cartilage degradation and bone erosion, and decreased serum levels of TNF-α, IL-1β, IL-8 in collagen-induced arthritis (CIA) mice; in further experiments, IL-6 levels were similarly reduced. The inhibitory effects of Antcin K upon TNF-α, IL-1β and IL-8 expression in human RASFs was achieved through the downregulation of the FAK, PI3K, AKT and NF-κB signaling cascades. Our data support clinical investigations using Antcin K in RA disease.
Highlights
Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease with a complex pathogenesis that is not fully understood, but is known to involve the infiltration of inflammatory cells into the joints and subsequent swelling, synoviocyte proliferation, cartilage damage and bone erosion [1, 2]
Long-term pharmacotherapy in rheumatoid arthritis (RA) disease is often associated with significant side effects, such as cytopenia, poor tolerability, rash, and occasionally liver damage occurring with traditional disease-modifying antirheumatic drugs (DMARDs) [7], while data from observational studies indicate higher risks of cardiovascular disease, infections, diabetes mellitus and mortality with glucocorticoids [8], and side effects relating to biologic treatment with tumor necrosis factor (TNF) inhibitors can include severe infection, sepsis, tuberculosis, lymphoma or demyelinating disorders [9]
Activated rheumatoid arthritis synovial fibroblast (RASF) exhibit a loss of contact inhibition [47] and accelerate the levels of adhesion molecules and proinflammatory cytokines including tumor necrosis factor alpha (TNF-a), interleukin 1 beta (IL-1b) and IL-8, causing synovial inflammation and cartilage damage [44]
Summary
Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease with a complex pathogenesis that is not fully understood, but is known to involve the infiltration of inflammatory cells into the joints and subsequent swelling, synoviocyte proliferation, cartilage damage and bone erosion [1, 2]. RASFs are considered to be the main catabolic factor in cartilage bone degradation, as they stimulate the production of proinflammatory cytokines typically associated with RA disease, including tumor necrosis factor alpha (TNF-a), interleukin 1 beta (IL-1b), IL-8 and IL-6 [5]. Long-term pharmacotherapy in RA disease is often associated with significant side effects, such as cytopenia, poor tolerability, rash, and occasionally liver damage occurring with traditional DMARDs [7], while data from observational studies indicate higher risks of cardiovascular disease, infections, diabetes mellitus and mortality with glucocorticoids [8], and side effects relating to biologic treatment with tumor necrosis factor (TNF) inhibitors can include severe infection, sepsis, tuberculosis, lymphoma or demyelinating disorders [9]
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