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

Xiaoling Qiang, Anthony S. Liotta, Joseph Shiloach, J. C. Gutierrez, Haichao Wang, Mahendar Ochani, Kanta Ochani, Huan Yang, Aviva Rabin, Derek LeRoith, Maxine A. Lesniak, Markus Böhm, Christian Maaser, Klaus Kannengiesser, Mark Donowitz, Shervin Rabizadeh, Christopher J. Czura, Kevin J. Tracey, Mark Westlake, Aida Zarfeshani, Syed F. Mehdi, Ann Danoff, Xueliang Ge, Suparna Sanyal, Gary J. Schwartz, Jesse Roth

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.