Overexpression of alpha(1)-acid glycoprotein in transgenic mice leads to sensitisation to acute colitis.
BACKGROUND
alpha(1)-Acid glycoprotein (alpha(1)-AGP) is an acute phase protein in most mammalian species whose concentration rises 2-5-fold during an acute phase reaction. Its serum concentration has often been used as a marker of disease, including inflammatory bowel disease (IBD). High alpha(1)-AGP levels were found to have a prognostic value for an increased risk of relapse in IBD.


OBJECTIVE
To investigate a possible role for increased serum levels of alpha(1)-AGP in the development of IBD.


METHODS
Dextran sodium sulphate (DSS) 2% was added to the drinking water of transgenic mice, overexpressing the rat alpha(1)-AGP gene, to induce acute colitis, thus mimicking the conditions of relapse. Clinical parameters, inflammatory parameters, and histological analyses on colon sections were performed.


RESULTS
Homozygous alpha(1)-AGP-transgenic mice started losing weight and showed rectal bleeding significantly earlier than heterozygous transgenic or wild-type mice. Survival time of homozygous transgenic mice was significantly shorter compared with heterozygous and wild-type mice. The higher susceptibility of homozygous alpha(1)-AGP-transgenic mice to DSS induced acute colitis was also reflected in higher local myeloperoxidase levels, higher inflammation scores of the colon, and higher systemic levels of interleukin 6 and serum amyloid P component. Local inflammatory parameters were also significantly different in heterozygous transgenic mice compared with wild-type mice, indicating a local dosage effect. In homozygous transgenic mice, significantly higher amounts of bacteria were found in organs but IgA levels were only slightly lower than those of control mice.


CONCLUSIONS
Sufficiently high serum levels of alpha(1)-AGP result in a more aggressive development of acute colitis.
Hochepied
T
T
Flanders Interuniversity Institute for Biotechnology and University of Ghent, Department of Molecular Biology, 9000 Ghent, Belgium.
Wullaert
A
A
Berger
F G
FG
Baumann
H
H
Brouckaert
P
P
Steidler
L
L
Libert
C
C
D000208:Acute Disease; D000818:Animals; D003092:Colitis / Q000097:blood* / Q000139:chemically induced; D015169:Colony Count, Microbial; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000097:blood; D007070:Immunoglobulin A / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009961:Orosomucoid / Q000378:metabolism*; D009195:Peroxidase / Q000097:blood; D000683:Serum Amyloid P-Component / Q000032:analysis; D015431:Weight Loss / Q000187:drug effects
D007070:Immunoglobulin A; D015850:Interleukin-6; D009961:Orosomucoid; D000683:Serum Amyloid P-Component; D016264:Dextran Sulfate; D009195:Peroxidase