A microbial metabolite, Lithocholic acid, suppresses IFN-γ and AhR expression by human cord blood CD4 T cells

Abstract

Declarations of interest: none Highlights• Lithocholic acid suppresses IFNγ production by CD4 T cells.• Lithocholic acid suppresses STAT1 and IRF1 expression by activated CD4 T cells.• Lithocholic acid suppresses AhR in a comparable manner to calcitriol. AbstractVitamin D is a well-known micronutrient that modulates immune responses by epigenetic and transcriptional regulation of target genes, such as inflammatory cytokines. Our group recently demonstrated that the most active form of vitamin D, calcitriol, reduces expression of a transcription factor known as the aryl hydrocarbon receptor (AhR) and inhibits differentiation of a pro-inflammatory T cell subset, Th9. Lithocholic acid (LCA), a secondary bile acid produced by commensal bacteria, is known to bind to and activate the vitamin D receptor (VDR) in a manner comparable to calcitriol. In this study, Naïve CD4 T cells were isolated from healthy human umbilical mononuclear cells and were stimulated in the presence or absence of LCA. We determined the effect of LCA on human cord blood T cell activation by measuring IFN-γ production and protein expression of IFN-γ receptor-mediated signaling molecules. We found that LCA reduces production of IFN-γ and decreases phosphorylation of STAT1 as well as expression of AhR, STAT1, and IRF1 by activated human cord blood CD4 T cells.LCA inhibits expression of IFN-g and reduces its receptor signaling molecules.

UniPR1331: Small Eph/Ephrin Antagonist Beneficial in Intestinal Inflammation by Interfering with Type-B Signaling

“…The selectivity of UniPR1331 had already been deeply investigated and the interaction with various targets of steroidal derivatives, like TGR5 and PXR [ 8 ], or with targets promoting cell proliferation or angiogenesis [ 11 ] had been excluded up to the concentration of 10 μM. However, a quite intriguing aspect is the documented ability of lithocholic acid, prototypical compound from which UniPR1331 stemmed, to interfere with adaptive immune responses: in particular, lithocholic acid was reported to hamper Th1 differentiation and the release of pro-inflammatory cytokines by Jurkat T cells and human/mouse CD4 + T cells [ 12 , 13 ]. Although unlikely, given the differences existing in the structure of the rigid core between the bile acid and the cholenic derivative UniPR1331, it is appealing to hypothesize that the anti-inflammatory action of UniPR1331 may ensue both from EphB/ephrin-B blockade and from the contribution of a component related to lithocholic acid.…”