Detection and function of posttranslationally modified ELR+CXC chemokines and chemokine-modifying enzymes.

Directional migration of leukocytes to a site of inflammation is coordinated by chemokines. Chemokines are small proteins that are locally secreted upon infection or tissue injury. As uncontrolled inflammation by excessive leukocyte recruitment leads to acute tissue destruction and chronic inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis, chemokine activity should be tightly regulated. This involves the rapid up-regulation of chemokine activity, but also the in time down-regulation upon resolution of infection. Chemokine activity is not only regulated by the amount of chemokine that is locally produced. Chemokine fine tuning is also achieved through enzyme-mediated posttranslational modifications. On the one hand, enzymatic processing of chemokines can activate precursor molecules or generate more active variants. On the other hand, processed chemokines can lose activity or even be inactivated. This project aims to study which chemokines interact with which enzymes (e.g. peptidyl arginine deiminase) and how this influences the activity of the chemokine. By optimizing a method to detect posttranslationally modified chemokines and the enzymes involved in body fluids, we will provide a realistic chemokine profile representative for the pathogenesis of inflammatory diseases, where disregulated enzyme activity might lead to inappropriate posttranslational modification of chemokines.

Keywords:Enzyme, Leukocyte migration, Posttranslational modification, Chemokine, Inflammation

Disciplines:Immunology