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Introduction High-dose intravenous immunoglobulin is a widely used therapeutic preparation. It is administered at high doses (1-2 grams per kilogram) for the suppression of autoantibody-triggered inflammation in a variety of clinical settings1. Immunoglobulin is a glycoprotein, composed of two identical heavy chains and two light chains, which in turn are composed of variable and constant domains. A minor population of IgG is glycosylated at Asn297 in the Fc domain, with glycans terminating in a-2,6 sialic acids (sFc)2-4. Recently, it has been reported that C-type lectins such as SIGN-R1 and human DC-SIGN recognize sFc of immunogloublin and mediate the suppression of autoantibody-mediated inflammation3. But the intracellular signaling mechanism of IVIG and its physiological meaning are not determined until now. Here, we identified that the binding of SIGN-R1/human DC-SIGN to IVIG rapidly generate ROS, leading to sequentially phosphorylate Protein X, P38 and NFkB. In particular, the phosphorylation of P38 and NFkB was dependent on the phosphorylation of Protein X. Also, it was verified that their binding induced anti-inflammatory cytokines such as IL-10 and IL-4 in vitro or in vivo. Currently, it is still in examination for the role of the SIGN-R1/human DC-SIGN-mediated signaling mechanism in the anti-inflammatory effects of IVIG. Although the further works are required, current results is important for unraveling a novel intracellular signaling mechanism of IVIG for its anti-inflammatory effects, which give an insight to develop a new therapy or plant-derived glycomimetic drugs to cure various inflammatory diseases or autoimmune disease.