Overexpression of α1-acid glycoprotein in transgenic mice leads to sensitisation to acute colitis

Abstract

Background: α1-Acid glycoprotein (α1-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 α1-AGP levels were found to have a prognostic value for an increased risk of relapse in IBD. Aims: To investigate a possible role for increased serum levels of α1-AGP in the development of IBD. Methods: Dextran sodium sulphate (DSS) 2% was added to the drinking water of transgenic mice, overexpressing the rat α1-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 α1-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 α1-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. Conclusion: Sufficiently high serum levels of α1-AGP result in a more aggressive development of acute colitis.