Effects of highly bioavailable 2,5-diketopiperazines in standardized extract of cultured Lentinula edodes mycelium (ECLM) on phagocytosis and inflammatory mediators production by J774A.1 macrophages

Abstract

A standardized extract of cultured Lentinula edodes mycelia (ECLM) has been reported to enhance innate and acquired immunity and suppress chronic inflammation. The present study revealed that the aqueous extract of ECLM significantly enhanced the phagocytic activity of J774A.1 macrophages. After fractionation, 23 distinct 2,5-diketopiperazines (DKPs) were identified in the active fraction, of which 12 were detected at concentrations≥1 μmol/kg or L in various samples from rats after oral administration of ECLM at 0.5 and 1.0 g/kg. These bioavail-able DKPs did not suppress phagocytosis in LPS-stimulated macrophages, whereas DKPs significantly suppressed LPS-induced NO and IL-6 productions. In the absence of LPS, these DKPs significantly enhanced phagocytosis in macrophages to levels similar to those achieved by the calcium sensing receptor (CaSR) allosteric agonist R-568, which was partially abolished by the CaSR allosteric antagonist NPS-2143. These facts indicate that DKPs in ECLM have dual roles in promoting innate immune responses without inducing proinflammatory responses, possibly via allosteric CaSR activation.