Gastric corticotropin-releasing factor influences mast cell infiltration in a rat model of functional dyspepsia

PLoS One. 2018 Sep 7;13(9):e0203704. doi: 10.1371/journal.pone.0203704. eCollection 2018.


Functional gastrointestinal disorders (FGIDs) are characterized by dysregulated gut-brain interactions. Emerging evidence shows that low-grade mucosal inflammation and immune activation contribute to FGIDs, including functional dyspepsia (FD). Stress plays an important role in the onset of FD symptoms. In human subjects with FD, presence of gastric mast cells has been reported, but factors that influence mast cell infiltration remain uncharacterized. Corticotropin-releasing factor (CRF) initiates the body's stress response and is known to degranulate mast cells. In this study, we delineated the role of the CRF system in the pathogenesis of FD in a rat model. Gastric irritation in neonate rat pups with iodoacetamide (IA) was used to induce FD-like symptoms. RNA interference (RNAi) was used to silence gastric CRF expression. Mast cell infiltrate in the stomach increased by 54% in IA-treated rats compared to controls and CRF-RNAi tended to decrease gastric mast cell infiltrate. Sucrose intake decreased in IA-treated rats and mast cell numbers showed a negative association with sucrose intake. IA treatment and transient silencing of gastric CRF increased hypothalamic CRF levels. In IA-treated rats, gastric levels of CRF receptor 2 (CRF2) decreased by ~76%, whereas hypothalamic CRF receptor 1 (CRF1) levels increased. Plasma levels of TNF-α showed a positive correlation with plasma CRF levels. Levels of phosphorylated p38 and ERK1/2 in the stomach showed a positive correlation with gastric CRF levels. Thus, CRF may contribute to low grade inflammation via modulating mast cell infiltration, cytokine levels, MAPK signaling, and the gut-brain axis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Cell Count
  • Corticotropin-Releasing Hormone / deficiency
  • Corticotropin-Releasing Hormone / genetics
  • Corticotropin-Releasing Hormone / metabolism*
  • Disease Models, Animal
  • Dyspepsia / immunology*
  • Dyspepsia / metabolism*
  • Dyspepsia / pathology
  • Dyspepsia / physiopathology
  • Gastric Mucosa / drug effects
  • Gastric Mucosa / metabolism*
  • Gastrointestinal Transit / drug effects
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Iodoacetamide / pharmacology
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mast Cells / cytology*
  • Mast Cells / drug effects
  • RNA Interference
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Tumor Necrosis Factor-alpha / metabolism


  • CRF receptor type 2
  • Receptors, Corticotropin-Releasing Hormone
  • Tumor Necrosis Factor-alpha
  • Corticotropin-Releasing Hormone
  • Iodoacetamide