Isoleucine, an Essential Amino Acid, Induces the Expression of Human <i>β</i> Defensin 2 through the Activation of the G-Protein Coupled Receptor-ERK Pathway in the Intestinal Epithelia

Abstract

Anti-microbial peptides are essential for the intestinal innate immunity that protects the intestinal epithelia from attacks by foreign pathogens. Human β-defensin (HBD) is one of the pivotal anti-microbial peptides that are expressed in the colonic epithelia. This study investigated the effect and the signaling mechanism of inducible β-defensin HBD2 by an essential amino acid, isoleucine (Ile) in colonic epithelial cells. Here we examined the expression level of HBD2 on induction of Ile in epithelial cells, and checked this pathway. HBD2 mRNA was induced by co-incubation with IL-1α and Ile in Caco2 cells, but not by Ile alone. An inhibitor of either ERK or Gi, a subunit of G-proteins, reduced the induction of HBD2 mRNA by Ile. The treatment with Ile also increased the intracellular calcium ion concentration, thus suggesting that the GPCR and ERK signaling pathway mediate the effects of Ile. These results indicate that an essential amino acid, Ile, enhances the expression of an inducible β-defensin, namely HBD2, by IL-1α through the activation of GPCRs and ERK signaling pathway. The administration of Ile may therefore represent a possible option to safely treat intestinal inflammation.

l-Isoleucine Administration Alleviates Rotavirus Infection and Immune Response in the Weaned Piglet Model

“…Recent studies have shown that isoleucine treatment can improve the immune functions of cells, animals and humans under normal and disease conditions ( 10 , 14 , 18 , 19 ). To initially understand the effect of isoleucine on innate immunity, we measured the expressions of innate immunity-relative genes after isoleucine treatment in IPEC-J2 and 3D4/31 cells.…”

“…3D4/31 cells were cultured in 6-well plates at 2.5 × 10 5 cells/well with RPMI 1640 medium added 10% FBS, 1% antibiotics, and 1 mM sodium pyruvate. According to some previous studies, different doses (0.4–10 mM) of isoleucine can affect the physiological functions in different cells ( 10 , 23 – 25 ). Combining with our pre-experiments, we found that 8 mM of isoleucine can regulate the mRNA expressions of some genes (data no published).…”

Longitudinal relationship of amino acids and indole metabolites with long-term body mass index and cardiometabolic risk markers in young individuals

“…Methionine, an aliphatic, sulfur-containing, essential amino acid exerts anti-inflammatory activity through the activation of endogenous antioxidant enzymes such as methionine sulfoxide reductase A, and by counteracting oxidative stress through the biosynthesis of glutathione 55 . Isoleucine, a branched chain amino acid exerts anti-inflammatory activity through interference with the action and/or synthesis of prostaglandins 56 , and inducing the expression of β-defensins via G-protein-coupling receptors and ERK/MAPK signaling pathways 57 . Tryptophan, an essential aromatic amino acid, plays a critical role in controlling systemic inflammatory responses through its endothelium-derived metabolite 5-methoxytryptophan 58 .…”

Functions and Signaling Pathways of Amino Acids in Intestinal Inflammation

“…However, high concentration of BCAAs increases oxidative stress and inflammation by mTOR and NF- κ B [ 114 ]; thus, diets with low Leu ameliorate symptoms of colitis and intestinal inflammation via the amino acid sensor GCN2 in colitis model [ 22 ]. Ile induces the expression of β -defensins via G-protein-coupling receptors (GPCRs) and ERK/MAPK signaling pathways [ 79 ]. And a recent study found that dietary Ile improves intestinal immune function, antioxidant capacity, and microbial population and regulates gene expression of antioxidant enzyme, tight junctions, Nrf2, p38, and ERK1 in the intestine of Jian carp [ 115 ].…”