Chromofungin (CHR: CHGA 47-66) is downregulated in persons with active ulcerative colitis and suppresses pro-inflammatory macrophage function through the inhibition of NF-κB signaling

Biochem Pharmacol. 2017 Dec 1;145:102-113. doi: 10.1016/j.bcp.2017.08.013. Epub 2017 Aug 19.

Abstract

Chromogranin-A (CHGA) is a prohormone secreted by neuroendocrine cells and is a precursor of several bioactive peptides, which are implicated in different and distinctive biological and immune functions. Chromofungin (CHR: CHGA47-66) is a short peptide with antimicrobial effects and encodes from CHGA exon-IV. Inflammatory bowel disease (IBD) is characterized by alterations in the activation of pro-inflammatory pathways, pro-inflammatory macrophages (M1), and nuclear transcription factor kappa B (NF-κB) signaling leading to the perpetuation of the inflammatory process. Here, we investigated the activity of CHR (CHGA Exon-IV) in persons with active ulcerative colitis (UC) and the underlying mechanisms in dextran sulfate sodium (DSS)-colitis in regard to macrophages activation and migration. Tissue mRNA expression of CHR (CHGA Exon-IV) was down regulated in active UC compared to healthy individuals and negatively correlated with pro-inflammatory macrophages (M1) cytokines, toll-like receptors (TLR)-4, and pNF-κB activity. In DSS colitis, CHR (CHGA Exon-IV) expression was reduced, and exogenous CHR treatment decreased the severity of colitis associated with a reduction of M1 macrophages markers and pNF-κB. In vitro, CHR treatment reduced macrophages migration, decreased pro-inflammatory cytokines production and pNF-κB. Targeting CHR may represent a promising new direction in research to define new therapeutic targets and biomarkers associated with IBD.

Keywords: C-Reactive Protein (PubChem CID: 126961377); Chromofungin, CgA(47-66) (PubChem SID: 26684380); Chromogranin-A; Chromogranin-A (PubChem SID: 178101855); Classically activated macrophages (M1); Dextran Sulfate Sodium (PubChem SID: 315501161); Gut hormones; IBD; Interleukin-1β (PubChem CID: 123872); Lipopolysaccharide (PubChem CID: 11970143); Mucosal Drug Action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromogranin A / metabolism*
  • Chromogranin A / pharmacology*
  • Colitis / chemically induced
  • Colitis, Ulcerative / metabolism*
  • Dextran Sulfate / toxicity
  • Down-Regulation
  • Gene Expression Regulation
  • Humans
  • Inflammation / metabolism*
  • Lipopolysaccharides / toxicity
  • Macrophages, Peritoneal / drug effects*
  • Male
  • Mice, Inbred C57BL
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Peptide Fragments / metabolism*
  • Peptide Fragments / pharmacology*
  • Signal Transduction

Substances

  • Chromogranin A
  • Lipopolysaccharides
  • NF-kappa B
  • Peptide Fragments
  • chromofungin
  • Dextran Sulfate

Grant support