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

ABSTRACT: Acute or chronic metabolic complications such as diabetic ketoacidosis are often associated with extracellular acidification and pancreatic ?-cell dysfunction. However, the mechanisms by which human ?-cells sense and respond to acidic pH remain elusive. In this study, using the recently developed human ?-cell line EndoC-?H2, we demonstrate that ?-cells respond to extracellular acidification through GPR68, which is the predominant proton sensing receptor of human ?-cells. Using gain- and loss-of-function studies, we provide evidence that the ?-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 ?-cells through NF-?B activation. Blocking of GPR68 or NF-?B activity severely attenuated acidification induced IL-8 production. Thus, we provide mechanistic insights into GPR68 mediated ?-cell response to acidic microenvironment, which could be a new target to protect ?-cell against acidosis induced inflammation.

SUBMITTER: Chandra V 

PROVIDER: S-EPMC4863151 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature