The chemokine RANTES is a crucial mediator of the progression from acute to chronic colitis in the rat

Chemokines have well characterized proinflammatory actions, including the a bility to induce extravasation of leukocytes that participate in chronic in flammation, In this study, we evaluated the role of a C-C chemokine, RANTES , in the chronic phase of a rat model of colitis. Colitis was induced by in tracolonic administration of trinitrobenzene sulfonic acid, At various time points thereafter (2 h to 14 days), colonic tissue levels of several chemok ines were measured. Unlike the expression of monocyte chemoattractant prote in-1, macrophage inflammatory protein-2, and cytokine-induced neutrophil ch emoattractant, the expression of RANTES was significantly elevated during t he chronic phase of colitis (greater than or equal to7 days after induction ). Colonic RANTES mRNA expression was also significantly elevated during th e chronic phase of colitis. The numbers of macrophages and monocytes in the colonic mucosa increased substantially during the chronic phase, as did ex pression of two of the receptors (CCR1 and CCR5) to which RANTES is known t o bind. Administration on days 7 through 14 after trinitrobenzene sulfonic acid administration of a CCR1/CCR5 receptor antagonist, Met-RANTES, resulte d in a significant reduction of both macroscopic and microscopic colonic da mage, as well as reducing the recruitment into the colon of monocytes, mast cells, and neutrophils. In some rats, treatment with Met-RANTES resulted i n a near-complete resolution of colonic damage and inflammation. These resu lts suggest a crucial role of RANTES in the progression from acute to chron ic inflammation in a rat model of colitis.