Cytosolic Double-Stranded DNA as a Damage-Associated Molecular Pattern Induces the Inflammatory Response in Rat Pancreatic Stellate Cells: A Plausible Mechanism for Tissue Injury-Associated Pancreatitis

Abstract

Pancreatitis is an inflammatory disease of unknown causes. There are many triggers causing pancreatitis, such as alcohol, common bile duct stone, virus and congenital or acquired stenosis of main pancreatic duct, which often involve tissue injuries. Pancreatitis often occurs in sterile condition, where the dead/dying pancreatic parenchymal cells and the necrotic tissues derived from self-digested-pancreas were observed. However, the causal relationship between tissue injury and pancreatitis and how tissue injury could induce the inflammation of the pancreas were not elucidated fully until now. This study demonstrates that cytosolic double-stranded DNA increases the expression of several inflammatory genes (cytokines, chemokines, type I interferon, and major histocompatibility complex) in rat pancreatic stellate cells. Furthermore, these increase accompanied the multiple signal molecules genes, such as interferon regulatory factors, nuclear factor-kappa B, low-molecular-weight protein 2, and transporter associated with antigen processing 1. We suggest that this phenomenon is a plausible mechanism that might explain how cell damage of the pancreas or tissue injury triggers acute, chronic, and autoimmune pancreatitis; it is potentially relevant to host immune responses induced during alcohol consumption or other causes.

Cross Talk Between Vascular Smooth Muscle Cells and Monocytes Through Interleukin-1β/Interleukin-18 Signaling Promotes Vein Graft Thickening

“…36 Genomic double-stranded DNA from dying cells induces inflammation in immune or nonimmune cells. [37][38][39] Thus, multiple damage-associated molecular patterns from the necrotic cell debris could contribute to the inflammasome activation we observed in this study.…”

ERK pathway and sheddases play an essential role in ethanol-induced CX3CL1 release in pancreatic stellate cells

“…31 For real-time reverse transcription-polymerase chain reaction (RT-PCR), 100 ng of total RNA was reverse transcribed into first-strand complementary DNA (cDNA) using a PrimeScript RT reagent kit (Takara Bio, Otsu, Shiga, Japan) according to the manufacturer's instructions and RT-PCR was performed using a LightCycler Real-Time PCR system (Roche, Switzerland) according to the manufacturer's instructions.…”

“…31 Briefly, unless otherwise noted, 10 mg of poly (I:C) was mixed with 5 ml of Lipofectamine 2000 and 985 ml of serum-free medium and incubated for 15 min at room temperature. A duplicate mixture without poly (I:C) and/or Lipofectamine 2000 was also incubated for 15 min at room temperature.…”

Pancreatic Stellate Cells and CX3CR1

“…Total RNA was extracted from the pancreatic tail and from PSCs using an RNeasy Mini Kit (Qiagen, Valencia, CA) as previously described 29,57 . Briefly, for RT-PCR, 100 ng of total RNA was reverse transcribed into first-strand complementary DNA (cDNA) using a PrimeScript RT Reagent Kit (Takara Bio, Inc, Otsu, Shiga, Japan) according to the manufacturer’s instructions.…”