Adenosine kinase inhibitor GP515 improves experimental colitis in mice.
Adenosine is a potent anti-inflammatory mediator. Through elevation of endogenous adenosine concentrations the adenosine kinase inhibitor GP515 might serve to down-regulate local inflammatory responses. In the present study we investigated the effect of systemic GP515 in the nonacute model of dextran sulfate sodium (DSS)-induced colitis. The clinical score, colon length, histologic score, colon cytokine production, and spleen weight from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving GP515 treatment were determined and compared with untreated control mice. Splenocytes were analyzed for phenotype, interferon-gamma (IFNgamma) production, and CD69 expression. First, GP515 treatment resulted in a significant improvement of clinical score (weight loss, stool consistency, and bleeding) and of histologic score. Second, colon shortening, an indirect parameter for the degree of inflammation, was decreased, consistent with a decreased IFNgamma concentration in the colonic tissue. Third, spleen weight was reduced in GP515-treated DSS mice. And fourth, IFNgamma synthesis and CD69 expression, as a marker for early cell activation, of ex vivo-stimulated splenocytes were suppressed in the GP515-treated DSS mice. These studies show that GP515 is effective in the therapy of DSS-induced colitis. One potential mechanism of action is the suppression of IFNgamma synthesis and CD69 expression. Adenosine kinase inhibition forms a pharmacologic target that should be further investigated for chronic inflammatory bowel disease.
Siegmund
B
B
Division of Clinical Pharmacology, Medizinische Klinik Innenstadt of the Ludwig-Maximilians-University, Munich, Germany.
Rieder
F
F
Albrich
S
S
Wolf
K
K
Bidlingmaier
C
C
Firestein
G S
GS
Boyle
D
D
Lehr
H A
HA
Loher
F
F
Hartmann
G
G
Endres
S
S
Eigler
A
A
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D005765:Gastrointestinal Agents / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis; D037181:Lectins, C-Type; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size; D012263:Ribonucleosides / Q000627:therapeutic use*; D013154:Spleen / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000099192:CD69 Antigens
D000248:Adenosine Kinase; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016264:Dextran Sulfate; D004791:Enzyme Inhibitors; D005765:Gastrointestinal Agents; D007371:Interferon-gamma; D037181:Lectins, C-Type; D012263:Ribonucleosides; D013755:Tetradecanoylphorbol Acetate; D000099192:CD69 Antigens; C087698:GP 1-515