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Abstract: Dendritic cells (DC) excel at presenting antigen to T cells and thus make a key contribution to the induction of primary and secondary immune responses. Sinomenine has been used for centuries in the treatment of patients with autoimmune diseases as it possesses immunosuppressive and anti-inflammatory activities. However, the effect of sinomenine on the differentiation, maturation, and functionality of DC derived from monocytes has not been studied. We show here that DC differentiation is promoted when monocytes are treated with GM-CSF and IL-4 (IL-4) in the presence of sinomenine (200 μg/ml), as evidenced by the upregulation of CD1a while CD14 was decreased. In addition, incubation of immature DC with sinomenine significantly blunted lipopolysaccharide (LPS)-induced DC maturation, as shown by the reduction of expression of the maturation marker CD83 and co-stimulatory molecules, including CD86, B7-H1, and CD40. Moreover, sinomenine also prevented decreases in antigen (FITC-Dextran or Lucifer Yellow) uptake by LPS-treated DC. Mixed lymphocyte reactions (MLRs) revealed that sinomenine-treated DC impede the secretion of the cytokines IL-2 and IFN-γ by co-cultured CD4+ T cells. Therefore, modulation of DC differentiation, maturation, and functionality by sinomenine is of potential relevance to its immunomodulatory effects in controlling specific immune responses in autoimmune diseases, transplantation, and other immune-mediated conditions. [Copyright &y& Elsevier]