Inflammatory Cytokines Trigger Higher Protein Levels as a Natural Defense Mechanism Against Disease

A new study from researchers at the University of Chicago provides important insight into how the pancreas protects itself during inflammation, pointing to promising new directions for treating pancreatitis.

Pancreatitis is a painful and sometimes life-threatening disease that occurs when the pancreas, an organ that helps digest food and regulate blood sugar, becomes inflamed. In severe cases, digestive enzymes that are normally safely stored inside the pancreas begin to damage the organ itself, a process known as "autodigestion." This can lead to chronic pain, scarring, and complications such as diabetes. Alcohol use, smoking, and genetics all contribute to pancreatitis, but scientists have struggled to understand how some genetic risk factors affect the disease.

The new study focuses on a gene called CLDN2, which produces a protein named claudin-2. It is part of a family of proteins that form tight junctions, which are microscopic seals between neighboring cells that control what can pass between them. Rather than forming a completely sealed barrier, some tight junction proteins act more like selective channels or pores, allowing specific substances to flow between cells.

"It's been known for quite some time that claudin-2 is involved in intestinal disease, and it tends to be increased as a consequence of inflammation," said Christopher Weber, MD, PhD, Professor of Pathology and one of the senior authors of the new study. "This is one of the first studies to show how claudin-2 affects pancreatitis as well."

The study, which was published recently in Gastroenterology, was co-led by Weber, Le Shen, MD, PhD, Research Associate Professor, and Scott Oakes, MD, Professor of Pathology and Vice Dean for Clinical Science Research.

A Protective Response to Inflammation

The researchers analyzed pancreatic tissue from patients with chronic pancreatitis as well as multiple mouse models of the disease. They found that claudin-2 levels are consistently higher in inflamed pancreatic tissue, especially in the cells lining the pancreatic ducts, the small tubes that carry digestive fluids out of the pancreas.

At first glance, this increase might seem harmful. But further experiments revealed that the rise in claudin-2 appears to be a protective response to disease, triggered by the release of chemical messengers called cytokines, including interferon-gamma (IFNγ).

To test whether claudin-2 actually protects the pancreas, the researchers studied mice engineered to lack the CLDN2 gene. Indeed, mice without claudin-2 developed more severe pancreatitis, with increased inflammation, greater tissue damage, and more scarring compared to normal mice. These findings were consistent across both short-term and chronic models of the disease.

A New Look at Pancreatic "Plumbing"

The study also sheds light on the fundamental but underappreciated process of how the pancreas moves fluid.

As the body digests food, the pancreas secretes fluid through its ducts, helping to deliver digestive enzymes and fluid safely into the intestine. This flow depends on coordinated movement of salts (ions like sodium and chloride) and water. Claudin-2 plays a critical role in this process by forming a channel that allows sodium ions and water to pass between cells.

The researchers developed pancreatic duct organoids, which are miniature, three-dimensional clusters of cells that mimic real tissue. Experiments with the organoids showed that claudin-2 is essential for fluid movement; when the protein was absent, the ducts were less able to secrete fluid. Without it, digestive enzymes can become more concentrated inside the pancreas, increasing the risk of damage and inflammation.

The study also showed that a gene called CFTR, which can cause cystic fibrosis when mutated, works in concert with claudin-2, ensuring proper pancreatic fluid production.

It turns out that claudin-2 is very important for maintaining liquidity of the fluid that dumps into the first part of the small intestine. Without it, you're going to have more concentrated digestive enzymes in the duct, which could predispose to pancreatitis."

Christopher Weber, The University of Chicago

Implications for Screening and Treatment

The findings offer a new perspective on pancreatitis and suggest potential therapeutic strategies. Instead of trying to suppress inflammation alone, future treatments might aim to boost the function of claudin-2 or improve pancreatic fluid secretion to prevent the buildup of harmful enzymes and reduce tissue damage.

The researchers also believe that mutations in the CLDN2 gene that impact fluid gatekeeping functions could be screened as a risk factor for pancreatitis.

"There are clinical genetic tests for pancreatitis, but claudin-2 often has not been included in the panel," Shen said. "Some people have started working on that, but hopefully this study can give it a further push to implement CLDN2 genetic testing for pancreatitis patients."