Abstract
Genetic deficiency in the expression of interleukin-10 (IL-10) is associated with the onset and progression of experimental inflammatory bowel disease (IBD). The clinical significance of IL-10 expression is supported by studies showing that immune-augmentation of IL-10 prevents inflammation and mucosal damage in animal models of colitis and in human colitis. Interleukin-10 (IL-10), an endogenous anti-inflammatory and immunomodulating cytokine, has been shown to prevent some inflammation and injury in animal and clinical studies, but the efficacy of IL-10 treatment remains unsatisfactory. We found that intra-peritoneal administration of adenoviral IL-10 to mice significantly reversed colitis induced by administration of 3% DSS (dextran sulfate), a common model of colitis. Adenoviral IL-10 (Ad-IL10) transfected mice developed high levels of IL-10 (394 +/- 136 pg/ml) within the peritoneal cavity where the adenovirus was expressed. Importantly, when given on day 4 (after the induction of colitis w/DSS), Ad-IL10 significantly reduced disease activity and weight loss and completely prevented histopathologic injury to the colon at day 10. Mechanistically, compared to Ad-null and DSS treated mice, Ad-IL10 and DSS-treated mice were able to suppress the expression of MAdCAM-1, an endothelial adhesion molecule associated with IBD. Our results suggest that Ad-IL10 (adenoviral IL-10) gene therapy of the intestine or peritoneum may be useful in the clinical treatment of IBD, since we demonstrated that this vector can reverse the course of an existing gut inflammation and markers of inflammation.
Highlights
Endothelial cell adhesion molecules ('ECAMs') play essential roles in the development of chronic inflammation by recruiting leukocytes, especially lymphocytes, to tissues
We found that compared to adeno-null or untreated mice, adenoviral IL-10 gene transfection after induction of clinical disease reversed the course of the disease induced by DSS (Figure 2)
Experimental colitis produced by DSS is thought to share many important characteristics with forms of human inflammatory bowel disease
Summary
Endothelial cell adhesion molecules ('ECAMs') play essential roles in the development of chronic inflammation by recruiting leukocytes, especially lymphocytes, to tissues. ECAMs support several forms of leukocyte adhesion including rolling, firm adhesion and extravasation [1]. Infiltration of tissues by leukocytes is a common hallmark of many chronic inflammatory states that include the inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD). In the setting of IBD, the expression of ECAMs like ICAM-1, VCAM-1, and MAdCAM-1 is observed in experimental models of colitis, and (page number not for citation purposes). ELISA measurement of IL-10 in peritoneal lavage fluids from control shows a very high level of expression of IL-10 at approximately 400 pg/ml. No IL-10 was detected in lavage fluids of control or adeno-null mice (n = 5)
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