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CCR9 Antagonists in the Treatment of Ulcerative Colitis.

Bekker P, Ebsworth K, Walters MJ, Berahovich RD, Ertl LS, Charvat TT, Punna S, Powers JP, Campbell JJ, Sullivan TJ, Jaen JC, Schall TJ - Mediators Inflamm. (2015)

Bottom Line: While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear.In the mdr1a(-/-) mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon.These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation.

View Article: PubMed Central - PubMed

Affiliation: ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, CA 94043, USA.

ABSTRACT
While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear. Toward this end, we compared colonic CCL25 protein levels in healthy individuals to those in patients with ulcerative colitis. In addition, we determined the effect of CCR9 pharmacological inhibition in the mdr1a(-/-) mouse model of ulcerative colitis. Colon samples from patients with ulcerative colitis had significantly higher levels of CCL25 protein compared to healthy controls, a finding mirrored in the mdr1a(-/-) mice. In the mdr1a(-/-) mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon. These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation.

No MeSH data available.


Related in: MedlinePlus

CCL25 protein is expressed in healthy human colon. Frozen sections of healthy human colon and small intestine were stained with CCL25 and isotype control antibodies. CCL25 protein was detected in epithelium in both colon and small bowel, as determined by IHC ((a), red color) and immunofluorescence ((b), green color). Magnification 100x (top row of (a)), 400x (bottom row of (a) and (b)).
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fig2: CCL25 protein is expressed in healthy human colon. Frozen sections of healthy human colon and small intestine were stained with CCL25 and isotype control antibodies. CCL25 protein was detected in epithelium in both colon and small bowel, as determined by IHC ((a), red color) and immunofluorescence ((b), green color). Magnification 100x (top row of (a)), 400x (bottom row of (a) and (b)).

Mentions: Normal small intestine and colon mRNA samples from different vendors were evaluated for CCL25 transcripts by Northern blot analysis. CCL25 mRNA was detected in all small intestine samples and in the majority (5 of 6) of colon samples (Figure 1). Immunohistochemical and immunofluorescence methods were utilized to determine whether CCL25 protein is expressed in normal colon. By each method, CCL25 protein was detected on epithelial cells in both the small bowel and colon (Figure 2).


CCR9 Antagonists in the Treatment of Ulcerative Colitis.

Bekker P, Ebsworth K, Walters MJ, Berahovich RD, Ertl LS, Charvat TT, Punna S, Powers JP, Campbell JJ, Sullivan TJ, Jaen JC, Schall TJ - Mediators Inflamm. (2015)

CCL25 protein is expressed in healthy human colon. Frozen sections of healthy human colon and small intestine were stained with CCL25 and isotype control antibodies. CCL25 protein was detected in epithelium in both colon and small bowel, as determined by IHC ((a), red color) and immunofluorescence ((b), green color). Magnification 100x (top row of (a)), 400x (bottom row of (a) and (b)).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4592714&req=5

fig2: CCL25 protein is expressed in healthy human colon. Frozen sections of healthy human colon and small intestine were stained with CCL25 and isotype control antibodies. CCL25 protein was detected in epithelium in both colon and small bowel, as determined by IHC ((a), red color) and immunofluorescence ((b), green color). Magnification 100x (top row of (a)), 400x (bottom row of (a) and (b)).
Mentions: Normal small intestine and colon mRNA samples from different vendors were evaluated for CCL25 transcripts by Northern blot analysis. CCL25 mRNA was detected in all small intestine samples and in the majority (5 of 6) of colon samples (Figure 1). Immunohistochemical and immunofluorescence methods were utilized to determine whether CCL25 protein is expressed in normal colon. By each method, CCL25 protein was detected on epithelial cells in both the small bowel and colon (Figure 2).

Bottom Line: While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear.In the mdr1a(-/-) mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon.These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation.

View Article: PubMed Central - PubMed

Affiliation: ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, CA 94043, USA.

ABSTRACT
While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear. Toward this end, we compared colonic CCL25 protein levels in healthy individuals to those in patients with ulcerative colitis. In addition, we determined the effect of CCR9 pharmacological inhibition in the mdr1a(-/-) mouse model of ulcerative colitis. Colon samples from patients with ulcerative colitis had significantly higher levels of CCL25 protein compared to healthy controls, a finding mirrored in the mdr1a(-/-) mice. In the mdr1a(-/-) mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon. These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation.

No MeSH data available.


Related in: MedlinePlus