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Background: Impaired expression and function of microRNAs (miRNAs) are involved in the pathogenesis of many autoimmune and inflammatory diseases. Moreover, there is a close relationship between TLRs and miRNAs and impairment in regulating their expression which can play a vital role in the immunopathogenesis of many inflammatory reactions. This research aimed to study the pharmaceutical effects of M2000 (ß-d-mannuronic acid) on the expression of miR-146a and its two target molecules (IRAK1 and TRAF6), and the transcription factor NF-?B in the HEK-Blue hTLR2 cell line. Methods: The cytotoxicity of M2000 was assessed by the MTT assay, and the qRT-PCR technique was employed in the presence and absence of M2000 treatment to measure gene-expression levels of miR-146a, IRAK1, TRAF6, and NF-?B. Results: MTT assay indicated that M2000 (before the concentration of 500 µg/ml) had no cytotoxic effect on HEK-Blue hTLR2 cells. Our results showed that M2000 at low and high doses (5 and 25 µg/well) could significantly reduce gene expression levels of miR-146a (p< 0.01). Furthermore, it was found that this medication at two different doses could considerably decrease IRAK1 and TRAF6 gene expression (p< 0.001). Moreover, this study revealed that expression level of NF-?B also significantly declined at these two doses (p< 0.01). Conclusions: This study for the first time shows that M2000 as a novel NSAID with immunosuppressive properties is able to modify TLR signaling through suppressing the adaptor molecules IRAK1 and TRAF6, the transcription factor NF-?B and miR-146a as a new therapeutic approach.