The role of β-d-mannuronic acid, as a new non-steroidal anti-inflammatory drug on expression of miR-146a, IRAK1, TRAF6, NF-κB and pro-inflammatory cytokines following a clinical trial in rheumatoid arthritis patients

Context: miR-146a, its targets (IRAK1, TRAF6) and NF-kappa B transcription factor play a fundamental role in rheumatoid arthritis (RA). Positive effects of drug beta-d-mannuronic acid (M2000) were proven on their expression in the HEK-Blue hTLR2 cell line, and results of its phase III clinical trial on RA patients were encouraging. Objective: This research aimed to investigate the effects of M2000 on expression of these genes and serum levels of IL-6 and TNF-alpha as pro-inflammatory cytokines in RA patients. Material and methods: In this study (Trial Registration Number: IRCT2017100213739N10), 12 RA patients (according to the American College of Rheumatology criteria) and 12 healthy subjects (as control group) were selected. The gene expression of miR-146a, IRAK1, TRAF6, and NF-kappa B were measured at the baseline and after 12 weeks M2000 therapy, using quantitative real-time PCR method. Moreover, the serum levels of IL-6 and TNF-alpha were evaluated at the similar times by ELISA method. Results: Our findings showed that the gene expression of miR-146a, IRAK1, TRAF6, and NF-kappa B significantly decreased after 12 weeks M2000 therapy in RA patients (0.81-, 0.68-, 0.79-, 0.82-fold, with p < .05, p < .01, p < .01, p < .05, respectively). Furthermore, the serum levels of IL-6 and TNF-alpha significantly reduced in these patients after 12 weeks M2000 therapy (both with p < .05). Conclusions: The present research results determined the part of molecular mechanisms of drug M2000 in RA treatment, based on the expression and function modification of miR-146a, IRAK1, TRAF6, NF-kappa B, IL-6 and TNF-alpha.