Abstract
Glycyrrhizin, an abundant bioactive component of the medicinal licorice root is rapidly metabolized by gut commensal bacteria into 18β-glycyrrhetinic acid (GRA). Either or both of these compounds have been shown to have antiviral, anti-hepatotoxic, anti-ulcerative, anti-tumor, anti-allergenic and anti-inflammatory activity in vitro or in vivo. In this study, the ability of GRA to modulate immune responses at the small intestinal mucosa when delivered orally was investigated. Analysis of cytokine transcription in duodenal and ileal tissue in response to GRA treatment revealed a pattern of chemokine and chemokine receptor gene expression predictive of B cell recruitment to the gut. Consistent with this finding, GRA induced increases in CD19+ B cells in the lamina propria and B220+ B cell aggregates framed by CD11c+ dendritic cells in structures resembling isolated lymphoid follicles (ILF). Using a mouse model of rotavirus infection, GRA reduced the duration of viral antigen shedding, and endpoint serum antibody titers were higher in GRA-treated animals. Together the data suggest GRA delivered orally augments lymphocyte recruitment to the intestinal mucosa and induces maturation of B cell-rich ILF independently of ectopic antigenic stimulus. These results provide further support a role for dietary ligands in modulation of dynamic intestinal lymphoid tissue.
Highlights
Active constituents in extracts of the medicinal licorice root include glycyrrhizin (GA) and its aglycone metabolite 18b-glycyrrhetinic acid (GRA)
Analysis of cell populations associated with isolated lymphoid follicles (ILF) formation in transgenic mice engineered to express CXCL13 in intestinal epithelial cells indicated a mechanism of CXCL13-mediated recruitment of B cells, as well as lymphoid tissue inducer (LTi)-like and NK cells to the gut mucosa [24]
In addition to the role of CXCL13 in ILF expansion and relevant to the gene expression induced by GRA, TLR activated LTi-like express LTa1LTb2 to interact with the LTbR on stromal cells, which in turn release cytokines including dendritic cell (DC) recruitment ligands CCL19 and CCL21, that together with other signals including IL-22, result in maturation of ILF and a T cell independent B cell response [32,33]
Summary
Active constituents in extracts of the medicinal licorice root include glycyrrhizin (GA) and its aglycone metabolite 18b-glycyrrhetinic acid (GRA). Multiple mechanisms of activity have been proposed including inductive or inhibitory effects on apoptosis, cytokine expression, intracellular signaling pathways, transcription factor activation, cellular membrane fluidity and modulation of oxidative stress [1,2,3,4,5,6]. How or if these mechanisms function in vivo to account for the ability of these compounds to attenuate pathology in infectious and inflammatory diseases is not well understood. GA-induced anti-inflammatory cytokine expression was demonstrated in a gut ischemia-reperfusion model [15]
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