New melanocortin-like peptide of E. coli can suppress inflammation via the mammalian melanocortin-1 receptor (MC1R): possible endocrine-like function for microbes of the gut

Abstract

E. coli releases a 33 amino acid peptide melanocortin-like peptide of E. coli (MECO-1) that is identical to the C-terminus of the E. coli elongation factor-G (EF-G) and has interesting similarities to two prominent mammalian melanocortin hormones, alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropin (ACTH). Note that MECO-1 lacks HFRW, the common pharmacophore of the known mammalian melanocortin peptides. MECO-1 and the two hormones were equally effective in severely blunting release of cytokines (HMGB1 and TNF) from macrophage-like cells in response to (i) endotoxin (lipopolysaccharide) or (ii) pro-inflammatory cytokine HMGB-1. The in vitro anti-inflammatoty effects of MECO-1 and of alpha-MSH were abrogated by (i) antibody against melanocortin-1 receptor (MC1R) and by (ii) agouti, an endogenous inverse agonist of MC1R. In vivo MECO-1 was even more potent than alpha-MSH in rescuing mice from death due to (i) lethal doses of LPS endotoxin or (ii) cecal ligation and puncture, models of sterile and infectious sepsis, respectively.

Commensal Hafnia alvei strain reduces food intake and fat mass in obese mice—a new potential probiotic for appetite and body weight management

“…The recovery of some other bacterial proteins by immunoprecipitation with α-MSH antibodies was due to their binding α-MSH-non related or possibly shorter α-MSH-like motifs which did not contain the melanocortin core sequence i.e., they cannot a priori activate the MCR. For instance, a mimicry of the α-MSH N-terminal was previously identified in the elongation factor-G of E.coli by the Roth's group using corticotropin antibodies [30]. We were also able to detect this protein in H.alvei after precipitation with an α-MSH antibody but it was about 600 times less abundant than the ClpB (data not shown).…”

Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: A paradigm shift for host–microbe interactions

“…In addition, we focused only on primary sequence homology between viral sequences and human hormones, and it is well known that hormones with different primary sequences but with similar tertiary structure may also be active in receptor binding and function. Along these lines, for example, using an ACTH immunoassay, Qiang et al (48) have identified a bacterial peptide fragment of Escherichia coli elongation factor-G that can mimic the antiinflammatory effects of α-melanocyte-stimulating hormone through the melanocortin-1 receptor. Likewise, by analysis of bacterial metagenomes, Cohen et al (49) have shown that gastrointestinal bacteria can produce N-acyl amides that bear structural similarities to ligand of G protein-coupled receptors and can mimic their effects on GLP-1 secretion and glucose homeostasis, although such ligands would not be found searching the primary sequences of the microbial genomes.…”

The effects of BMS-470539 on lipopolysaccharide-induced acute lung injury

“…According to previous reports, α-MSH exerts its anti-inflammatory effects by inhibiting nitric oxide synthesis in murine macrophages [21], by inhibiting neutrophil migration to inflammatory sites in vitro in human neutrophils [22], by reducing the release of TNF-α and interleukin-1 in lipopolysaccharide-induced mouse serum [23], and by upregulating interleukin-10 in human monocytes [24]. Several reports have suggested that peptide compounds specific for MC1R exert anti-inflammatory effects that are reduced by α-MSH [7,10,11,13,14]. Thus, we evaluated the antiinflammatory effects of BMS-470539, a selective MC1R agonist peptide, on lipopolysaccharide-induced ALI.…”

“…MC1R activation has been implicated in the restoration of inflammatory response homeostasis, as it has been detected in various immune cells, including monocytes, neutrophils, macrophages, cytotoxic T cells, and dendritic cells [7,9]. In several studies, MC1R targeting has shown anti-inflammatory and immunomodulatory effects [7,10-14]. Among these studies, BMS-470539, a selective MC1R agonist, has emerged as a promising anti-inflammatory candidate that inhibits neutrophil recruitment and, leukocyte migration in the lung [7,10,12].…”