Melatonin attenuates TNF‐α and IL‐1β expression in synovial fibroblasts and diminishes cartilage degradation: Implications for the treatment of rheumatoid arthritis

Abstract

The hormone melatonin has many properties, including antioxidant, anti‐inflammatory, and immunomodulatory effects. Melatonin has been demonstrated to be beneficial in several inflammatory autoimmune diseases, but its effects in rheumatoid arthritis (RA) remain controversial. We sought to determine how melatonin regulates inflammation in RA. We found that melatonin dose‐dependently inhibits tumor necrosis factor‐α (TNF‐α) and interleukin (IL)‐1β expression through the PI3K/AKT, ERK, and NF‐κB signaling pathways. We also identified that melatonin inhibits TNF‐α and IL‐1β production by upregulating miR‐3150a‐3p expression. Synovial tissue specimens from RA patients and culture of human rheumatoid fibroblast‐like synoviocytes confirmed that the MT1 receptor is needed for the anti‐inflammatory activities of melatonin. Importantly, melatonin also significantly reduced paw swelling, cartilage degradation, and bone erosion in the collagen‐induced arthritis mouse model. Our results indicate that melatonin ameliorates RA by inhibiting TNF‐α and IL‐1β production through downregulation of the PI3K/AKT, ERK, NF‐κB signaling pathways, as well as miR‐3150a‐3p overexpression. The role of melatonin as an adjuvant treatment in patients with RA deserves further clinical studies.

High plasma levels of pro-inflammatory factors interleukin-17 and interleukin-23 are associated with poor outcome of cardiac-arrest patients: a single center experience

“…Bro-Jeppesen et al reported baseline plasma IL-6 and IL-10 levels were significantly higher in non-survivors compared with survivors [11,12]. Melatonin, an anti-oxidant and anti-inflammatory agent, improves neurological outcomes and preserves hippocampal mitochondrial function in cardiac arrest [36], which may be associated with its protection against inflammation [22,[37][38][39], myocardial ischemia-reperfusion injury [40][41][42][43], ventricular fibrillation [44], cardiac hypertrophy [45], dilated cardiomyopathy [46], and mitochondria-related disorders [47,48]. As neutralization of IL-17 rescues neuroinflammation [49], melatonin may contribute to the complex role of IL-17 signaling in ROSC [50].…”

Reconsidering the Role of Melatonin in Rheumatoid Arthritis

“…A positive correlation has been observed between the polymorphism of the melatonin receptor type 1B (MTNR1B) and levels of rheumatoid factor in Korean patients with RA [19]. Other researchers have reported significantly lower levels of MT 1 expression in RA synovial tissue compared with normal healthy tissue, and the finding that siRNAs against MT 1 reverse melatonin-mediated inhibition of TNF-α and IL-1β production, confirming that melatonin suppresses TNF-α and IL-1β via the MT 1 receptor [20]. Thus, the activity of membrane melatonin receptors and their specific agonists is implicated in circadian rhythmicity [7].…”

“…A recent study found that melatonin appears to inhibit miR-590-3p expression and induce apoptosis in human osteoblasts [55]. In another study, melatonin treatment effectively downregulated TNF-α and IL-1β production in human RA synovial fibroblasts (the MH7A cell line) by suppressing PI3K/AKT, ERK, and NF-κB signaling and upregulating miR-3150a-3p expression [20]. Those investigations confirmed that the MT 1 receptor mediates the anti-inflammatory effects of melatonin and that melatonin not only inhibits inflammatory cytokine release in mice with CIA-induced arthritis, but also attenuates CIA-induced cartilage degradation and bone erosion [20].…”

“…Research demonstrating that melatonin dose-dependently inhibits the proliferation of RA fibroblast-like synoviocytes (FLS) through the activation of the ERK/P21/P27 pathway suggests that inhibiting the invasion of RA FLS through cartilage and into bone may have important implications in the treatment of RA [48]. Blocking NF-κB signaling appears to be the way in which melatonin protects cells from oxidative stress [28] and largely explains how melatonin suppresses proinflammatory cytokines such as IL-1β and TNF-α [20]. Other pathways and molecules associated with inflammation that are modulated by melatonin include the mitogen-activated protein kinase (MAPK) and nuclear erythroid 2-related factor 2 (Nrf2) pathways, as well as Toll-like receptors [15].…”

Melatonin stimulates extracellular matrix formation in human articular cartilage chondrocytes

“…In the cartilage, the activities of melatonin have been observed in normal and pathological processes such as osteoarthritis (9) or intervertebral disc degeneration, where melatonin acts via Sirt1 expression (10). Moreover, melatonin can ameliorate rheumatoid arthritis reducing inflammation, limiting cartilage degradation and bone erosion (11).…”