P010. The effect of interleukin-1 receptor antagonism in the management of intestinal inflammation; an in vitro and in vivo study
K. Arvanitidis1, E. Filidou1, V. Valatas2, E. Kouroumalis2, V. Paspaliaris3, G. Kolios1, 1Faculty of Medicine, Democritus University of Thrace, Laboratory of Pharmacology, Alexandropoulis, Greece, 2Medical Department, University of Crete, Gastroenterology Laboratory, Heraklion, Greece, 3Itis Pharmaceuticals Pty Ltd, Melbourne, Australia
Increased levels of interleukin-1 (IL-1) and reduced levels of IL-1 receptor antagonist (IL-1ra), have been found in patients with inflammatory bowel disease (IBD). IP-1510 is a new synthetic peptide, antagonist of interleukin 1 receptor. Phase I/II studies of this peptide in the management of Cancer-Related Cachexia have shown that it was well tolerated and safe in advanced cancer patients and it induced statistically significant improvement in anorexia of patients. The aim of this study was to determine in vitro and in vivo the effect of Interleukin-1 receptor antagonism in the management of intestinal inflammation, using IP-1510, a novel IL-1ra.
Two human colonic epithelial cell lines (HT-29, CaCO-2) were used for the in vitro studies. Cells were treated with IL-1alpha and IL-1beta added alone or in combination with the pro-inflammatory cytokines TNF-alpha and IFN-gamma in the presence of various concentrations of both isomers (L and D) of IP-1510 and inflammatory mediators measured in supernatants. A model of DSS colitis, using C57BL/6 female mice, was used to examine in vivo the effect of the isomers of IP-1510 on experimental colitis. 2.5ug of IP-1510 were given intraperitoneally every 48 hours to mice treated with 3.5% DSS daily and weight loss and macroscopic and histological evaluation of colitis performed to IP-1510 treated DSS mice and controls.
The presence of IP-1510 in colonic epithelial cell cultures was found to positively modulate inflammatory mediators production induced by IL-1alpha and IL-1beta, added alone or in combination with pro-inflammatory cytokines, reducing statistically significantly certain mediators such as IL-8 and IL-17 in a dose dependent manner (p < 0.01). DSS treatment was found to induce weight loss and histologically proved colitis in mice. DSS colitis mice treated with IP-1510, while in an early phase have a similar weight loss with untreated DSS colitis animals, they showed a significant improvement, regarding weight loss and colitis, at the end of the experimental procedure, compared to untreated DSS colitis animals, indicating a beneficial effect of IP-1510 on DSS-induced colitis.
These data from our in vitro and in vivo study demonstrate that Interleukin-1 receptor antagonism might play a crucial role in the management of the intestinal inflammation and antagonists of IL-1 receptor, such as IP-1510, require further study for their possible therapeutic effect in IBD.