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*
Mucosal Inflammation Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada;
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and
Serono Pharmaceutical Institute, Geneva, Switzerland
Chemokines have well characterized proinflammatory actions,
including the ability to induce extravasation of leukocytes that
participate in chronic inflammation. 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 intracolonic administration of
trinitrobenzene sulfonic acid. At various timepoints thereafter (2 h to
14 days), colonic tissue levels of several chemokines were measured.
Unlike the expression of monocyte chemoattractant protein-1, macrophage
inflammatory protein-2, and cytokine-induced neutrophil
chemoattractant, the expression of RANTES was significantly elevated
during the chronic phase of colitis (
7 days after induction). Colonic
RANTES mRNA expression was also significantly elevated during the
chronic phase of colitis. The numbers of macrophages and monocytes in
the colonic mucosa increased substantially during the chronic phase, as
did expression of two of the receptors (CCR1 and CCR5) to which RANTES
is known to bind. Administration on days 7 through 14 after
trinitrobenzene sulfonic acid administration of a CCR1/CCR5 receptor
antagonist, Met-RANTES, resulted in a significant reduction of both
macroscopic and microscopic colonic damage, as well as reducing the
recruitment into the colon of monocytes, mast cells, and neutrophils.
In some rats, treatment with Met-RANTES resulted in a near-complete
resolution of colonic damage and inflammation. These results suggest a
crucial role of RANTES in the progression from acute to chronic
inflammation in a rat model of colitis.
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