The digestive system has to deal with the intrusion of all kinds of foreign matter – billions of bacteria and many different food products. One of the great mysteries in immunology is how the gut is able to decide when an invading body is a real threat or a benign substance. Robin Lorenz and colleagues from Washington University School of Medicine, St Louis, Missouri, have just discovered that an enzyme called cyclooxygenase-2 (or COX-2 for short) may be an important factor in promoting 'oral tolerance'- whereby a visitor in the digestive system is accepted rather than attacked.

Foreign substances can be recognised by certain cells of the immune system – T cells – which hang out all over the body, including in the lining of the digestive tract. Depending on the molecules they recognise as familiar, these cells organise either a so-called 'Th3' response, which keeps the rest of the immune system on a leash , or a 'pathogenic' response, which announces that a fight is on against an invader. Part of the pathogenic response to a foreign substance in the digestive system triggers an inflammation of the intestines.

Lorenz and colleagues, reporting in Nature Medicine [August 1999], studied mice that had been manipulated so that their T cells could recognise only one foreign substance – egg-white lysozyme. Much to the surprise of the researchers, when they fed egg-white lysozyme to the mice there was no immune response, even though every T cell was primed to recognise this one protein. However, if they administered lysozyme together with a drug that blocks the action of COX-2, there was a strong inflammatory reaction, with visible swelling of the small intestines.

The gut of these mice with disabled COX-2 looked very similar to that of humans with certain digestive-tract diseases, such as inflammatory bowel disease or coeliac disease (which results from sensitivity to an ingredient – gluten – found in some grains), where the immune system in the gut responds incorrectly to the presence of friendly foreigners, causing irritation and inflammation.

The experiments of Lorenz and colleagues indicate that COX-2 exerts some anti-inflammatory effect in the digestive system. It seems to be needed to help keep the immune response in balance – an important function, given the distress caused by inflammatory bowel disease for example.

What makes this idea about an anti-inflammatory role for COX-2 controversial is that it has always been viewed as an agent that promotes an inflammatory response. A lot of energy has gone into finding ways to block the activity of COX-2 in order to decrease inflammation. For example, two blockers of COX-2, Celebrex and Vioxx, have recently hit the market that are used to ease the inflammation and pain associated with rheumatoid and osteoarthritis.

COX-2 has a partner, COX-1, which, along with COX-2, is inhibited by general anti-inflammatory agents, such as asprin. But these non-steroidal anti-inflammatory drugs (known as NSAIDS) like aspirin are hard on the gut because they irritate the lining of the stomach and intestines.

The hope was that a COX-2 inhibitor could bring pain relief without having negative effects on the digestive system. "Many people put on COX-2 inhibitors in clinics will already have been on NSAIDs for a long time and already have irritation and inflammation in their digestive systems," explains Derek Willoughby of St Bartholomew's and Royal Hospital School of Medicine and Dentistry, London, UK. The new information suggesting that COX-2 has an anti-inflammatory effect on the gut lining raises questions about the true role of this substance in regulating the immune response, and also about the long-term effects of COX-2 inhibitors on the digestive tract.