Extracellular acidification stimulates GPR68 mediated IL-8 production in human pancreatic β cells

Sci Rep. 2016 May 11;6:25765. doi: 10.1038/srep25765.

Abstract

Acute or chronic metabolic complications such as diabetic ketoacidosis are often associated with extracellular acidification and pancreatic β-cell dysfunction. However, the mechanisms by which human β-cells sense and respond to acidic pH remain elusive. In this study, using the recently developed human β-cell line EndoC-βH2, we demonstrate that β-cells respond to extracellular acidification through GPR68, which is the predominant proton sensing receptor of human β-cells. Using gain- and loss-of-function studies, we provide evidence that the β-cell enriched transcription factor RFX6 is a major regulator of GPR68. Further, we show that acidic pH stimulates the production and secretion of the chemokine IL-8 by β-cells through NF-кB activation. Blocking of GPR68 or NF-кB activity severely attenuated acidification induced IL-8 production. Thus, we provide mechanistic insights into GPR68 mediated β-cell response to acidic microenvironment, which could be a new target to protect β-cell against acidosis induced inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acids / metabolism*
  • Cell Line
  • Cyclic AMP / biosynthesis
  • Extracellular Space / chemistry*
  • Humans
  • Hydrogen-Ion Concentration
  • Inflammation Mediators / metabolism
  • Inositol Phosphates / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Interleukin-8 / biosynthesis*
  • NF-kappa B / metabolism
  • Neutrophils / metabolism
  • Protons
  • Receptors, G-Protein-Coupled / metabolism*
  • Regulatory Factor X Transcription Factors / metabolism

Substances

  • Acids
  • GPR68 protein, human
  • Inflammation Mediators
  • Inositol Phosphates
  • Interleukin-8
  • NF-kappa B
  • Protons
  • Receptors, G-Protein-Coupled
  • Regulatory Factor X Transcription Factors
  • Rfx6 protein, human
  • Cyclic AMP