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Notes: Background Recognition of foreign substances by innate immunity through pattern recognition receptors (PRRs) regulates acquired immunity such as allergic reaction. Because PRRs recognize heterogeneous ligands, daily food intake can potentially regulate immune allergic reaction.Objective Elucidation of the effect of λ-carrageenan on allergic reactions was aimed.Method IFN-γ and IL-4 was measured in in vitro T cell-stimulated culture. Cytokine production from macrophages in response to λ-carrageenan was measured as indicator for innate immunity activation. Mice were immunized with OVA in alum to induce specific IgE, and then histamine release was induced by systemic injection of OVA.Results Activation of innate immunity by λ-carrageenan is dependent on Toll-like receptor-4 (TLR4) and MyD88, in which induction of pro-inflammatory cytokines such as TNF-α and IL-6 was largely impaired in macrophages from TLR4- and MyD88-deficient mice. Footpad oedema, a model for in vivo inflammatory reactions, was significantly reduced in these mice. Similar to recent evidence showing a preference for the stimulation of Th1 via TLR/MyD88 signalling, λ-carrageenan showed enhanced IFN-γ and decreased IL-4 in stimulated T cell cultures. Interestingly, increased IFN-γ production was still seen in TLR4- and MyD88-deficient splenocytes. Oral administration of λ-carrageenan to immunized mice successfully decreased OVA-specific IgE, and λ-carrageenan was also effective in previously immunized mice. Further, serum histamine release upon systemic challenge of OVA was significantly inhibited. Neither OVA-specific IgG1/IgG2a nor cytokine secretion from in vitro cultures were altered, suggesting the involvement of multiple PRRs as demonstrated by TLR4/MyD88-independent IFN-γ up-regulation. The simultaneous feeding of OVA with lipopolysaccharide abrogated oral tolerance, but λ-carrageenan was not only devoid of such an effect but was also found to promote oral tolerance in the absence of TLR4.Conclusion λ-Carrageenan was suggested to be a useful dietary supplement to ameliorate allergic reactions while maintaining oral tolerance-dependent intestinal homeostasis.