The role of mast cells in inflammatory disease

Mast cells are recognized as key effector cells in allergic inflammation. Activation of mast cells results in the release of several powerful inflammatory mediators, e.g. histamine, arachidonic acid metabolites, cytokines, heparin proteoglycans, carboxypeptidase and various serine proteases.Mast cell serine proteases are either chymases (chymotrypsin-like) or tryptases (trypsin-like). The biological function of these proteases is largely unknown, although their high abundance at sites of mast cell activation suggests an important role in the inflammatory response.

The aim of the project is to gain further insight into the role of mast cell serine proteases in allergic inflammation and we believe that increased knowledge of the biology of these proteases may lead to improved treatment for allergic disease. We have previously purified and characterized several mast cell chymases. Mast cell chymase was found to be recovered in a tight macromolecular complex with heparin proteoglycan. The binding of heparin to chymase results in activation of the enzyme and resistance of the chymase towards protease inhibition. Mast cell chymase in complex with heparin proteoglycan was found to degrade and thereby inactivate thrombin, suggesting a role for chymase in regulation of coagulation.

Recently, we have cloned a large number of different mast cell proteases and the project will now focus on:

• Expression of various mast cell proteases in an active form, to allow functional studies of these enzymes.
• Determination of the in vivo effects of mast cell proteases in relation to inflammatory responses.
• Designing of specific inhibitors for different mast cell proteases, and to determine whether such inhibitors are capable of modulating allergic reactions.