CCL2 (pM levels) as a therapeutic agent in Inflammatory Bowel Disease models in mice.
BACKGROUND
Chemokines regulate the pathways that restrict homing of specific subsets of immune cells, and thereby fine tune the immune response at specific lymphoid and peripheral tissues. CCL2 is a chemokine that induces migration of monocytes, memory T cells, and dendritic cells. Previously, we demonstrated that pM levels of CCL2 dramatically inhibit migration of T cells. The aim was to test whether subphysiological doses of CCL2 can ameliorate murine colitis and inflammation-induced colorectal cancer.


METHODS
TNBS (2,4,6 trinitrobenzene sulfonic acid) colitis and dextran sodium sulfate (DSS) colitis were induced in Balb/c and C57BL/6 mice, respectively. Mice were treated daily with intraperitoneal CCL2 injections. Disease activity was assessed clinically, histologically, and by measuring inflammatory cytokine levels. In addition, an inflammatory cancer model was induced by azoxymethane-DSS (AOM-DSS) in Balb/c mice. Mice were treated daily with CCL2 for 11 weeks and then assessed for number of tumors in the colons.


RESULTS
Daily administration of CCL2 (60-120 ng) significantly decreased the development of TNBS- and DSS-induced colitis. In a DSS-AOM model, CCL2-treated mice developed significantly fewer tumors (P < 0.005) at 11 weeks. Chronic inflammation in the CCL2-treated mice was significantly less pronounced as compared to phosphate-buffered saline-treated mice.


CONCLUSIONS
Administration of pM levels of CCL2 significantly inhibits migration of T cells in amelioration of TNBS and DSS colitis and inhibits development of colorectal cancer in an AOM-DSS colitis model in mice. Thus, pM levels of CCL2 may be clinically beneficial as an antiinflammatory agent in IBD.
Maharshak
N
N
Department of Immunology, the Weizmann Institute of Science, Rehovot, Israel.
Hart
G
G
Ron
E
E
Zelman
E
E
Sagiv
A
A
Arber
N
N
Brazowski
E
E
Margalit
R
R
Elinav
E
E
Shachar
I
I
D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000627:therapeutic use*; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007124:Immunoenzyme Techniques; D015212:Inflammatory Bowel Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
D002273:Carcinogens; D018932:Chemokine CCL2; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D001397:Azoxymethane