Impact of Multiple Chemokine Expression in Human Disease

Chemokines are secreted proteins of 67 to 127 amino acids and have emerged as key controllers of cell migration. Most chemokines are produced under pathological conditions and attract leukocytes into inflamed tissues. Several chemokines, however, are produced constitutively and regulate lymphocyte traffic and homing, especially into lymph nodes. The study has tested the hypothesis that chemokines can induce additional regulatory mechanisms for leukocyte migration and activation besides their “classical” activity induced by agonist/receptor interactions. We have provided evidence for three additional modes of chemokine-mediated leukocyte regulation: antagonism, repulsion, and synergism. The first two mechanisms have been described by our group and others in the recent years. During the timeframe of this project, we have extended the study on natural antagonists, and found an additional mechanism govern by synergy-inducing chemokines. This is a novel regulatory mechanism with potentially far-reaching and profound consequences for our understanding of leukocyte migration and activation. In addition, we have shown that chemokines acting in synergism are expressed concomitantly during chronic inflammatory conditions, such as Rheumatoid Arthritis and Contact Dermatitis.