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*
Gastrointestinal Unit, Department of Medicine, Center for the Study of Inflammatory Bowel Disease, and
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC;
§
Department of Molecular Genetics and Microbiology and Institute for Cellular and Molecular Biology, University of Texas, Austin, TX 78712; and
¶
Division of Gastroenterology, Albany Medical College, Albany, NY 12208
The chemokine receptors CCR2 and CCR5 and their respective ligands
regulate leukocyte chemotaxis and activation. To determine the role of
these chemokine receptors in the regulation of the intestinal immune
response, we induced colitis in CCR2- and CCR5-deficient mice by
continuous oral administration of dextran sodium sulfate (DSS). Both
CCR2- and CCR5-deficient mice were susceptible to DSS-induced
intestinal inflammation. The lack of CCR2 or CCR5 did not reduce the
DSS-induced migration of macrophages into the colonic lamina propria.
However, both CCR5-deficient mice and, to a lesser degree,
CCR2-deficient mice were protected from DSS-induced intestinal
adhesions and mucosal ulcerations. CCR5-deficient mice were
characterized by a greater relative infiltration of CD4+
and NK1.1+ lymphocyte in the colonic lamina propria when
compared to wild-type and CCR2-deficient mice. In CCR5-deficient mice,
mucosal mRNA expression of IL-4, IL-5, and IL-10 was increased, whereas
that of IFN-
was decreased, corresponding to a Th2 pattern of T cell
activation. In CCR2-deficient mice, the infiltration of Th2-type T
cells in the lamina propria was absent, but increased levels of IL-10
and decreased levels of IFN- may have down regulated mucosal
inflammation. Our data indicate that CCR5 may be critical for the
promotion of intestinal Th1-type immune responses in
mice.
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