Intestinal alkaline phosphatase has beneficial effects in mouse models of chronic colitis.
BACKGROUND
The brush border enzyme intestinal alkaline phosphatase (IAP) functions as a gut mucosal defense factor and is protective against dextran sulfate sodium (DSS)-induced acute injury in rats. The present study evaluated the potential therapeutic role for orally administered calf IAP (cIAP) in two independent mouse models of chronic colitis: 1) DSS-induced chronic colitis, and 2) chronic spontaneous colitis in Wiskott-Aldrich Syndrome protein (WASP)-deficient (knockout) mice that is accelerated by irradiation.


METHODS
The wildtype (WT) and IAP knockout (IAP-KO) mice received four cycles of 2% DSS ad libitum for 7 days. Each cycle was followed by a 7-day DSS-free interval during which mice received either cIAP or vehicle in the drinking water. The WASP-KO mice received either vehicle or cIAP for 6 weeks beginning on the day of irradiation.


RESULTS
Microscopic colitis scores of DSS-treated IAP-KO mice were higher than DSS-treated WT mice (52±3.8 versus 28.8±6.6, respectively, P<0.0001). cIAP treatment attenuated the disease in both groups (KO=30.7±6.01, WT=18.7±5.0, P<0.05). In irradiated WASP-KO mice cIAP also attenuated colitis compared to control groups (3.3±0.52 versus 6.2±0.34, respectively, P<0.001). Tissue myeloperoxidase activity and proinflammatory cytokines were significantly decreased by cIAP treatment.


CONCLUSIONS
Endogenous IAP appears to play a role in protecting the host against chronic colitis. Orally administered cIAP exerts a protective effect in two independent mouse models of chronic colitis and may represent a novel therapy for human IBD.
Ramasamy
Sundaram
S
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Nguyen
Deanna D
DD
Eston
Michelle A
MA
Alam
Sayeda Nasrin
SN
Moss
Angela K
AK
Ebrahimi
Farzad
F
Biswas
Brishti
B
Mostafa
Golam
G
Chen
Kathryn T
KT
Kaliannan
Kanakaraju
K
Yammine
Halim
H
Narisawa
Sonoko
S
Millán
José Luis
JL
Warren
H Shaw
HS
Hohmann
Elizabeth L
EL
Mizoguchi
Emiko
E
Reinecker
Hans-Christian
HC
Bhan
Atul K
AK
Snapper
Scott B
SB
Malo
Madhu S
MS
Hodin
Richard A
RA
D000469:Alkaline Phosphatase / Q000008:administration & dosage*; D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009195:Peroxidase / Q000378:metabolism; D014923:Wiskott-Aldrich Syndrome; D051316:Wiskott-Aldrich Syndrome Protein / Q000502:physiology
D016207:Cytokines; D051316:Wiskott-Aldrich Syndrome Protein; D016264:Dextran Sulfate; D009195:Peroxidase; D000469:Alkaline Phosphatase