S1747 Corticotropin Releasing Factor Overexpressing (CRF-OE) Mice Display Upregulation of Proinflammatory Markers in the Colon: A Possible Implication in the Influence of Chronic Stress on the Inflammatory Bowel Diseases (IBD)

Abstract

Background: Stress has an impact on disease flares, with the majority of IBD patients endorsing a link between their illness and stress (Am J Gastroenterol 2006; 101:775). Chronic stress was also found to be strongly predictive of subsequent IBD relapse (Health Psychol 2002; 21:531; Gut 2008; 57:1386). CRF is a key mediator of stress response and CRF-OE mice showed chronic stress-like neuroendocrine, autonomic and immunological changes and are a valid animal model for chronic stress (Peptides 2001; 22:733). CRF deficiency reduced colonic inflammation in a mouse model of experimental colitis (Endocrinology 2008; 149:3403). Aims: 1. To characterize CRF gene expression and upregulation in the colon in transgenic mice overexpressing CRF compared with the hypothalamus. 2. To assess gene expression of proand anti-inflammatory markers in the mouse colon under CRF overexpression as a chronic stress condition. Methods: The proximal colon and hypothalamus were collected from female CRF-OE mice and their wild type (WT) littermates (Oregon Health and Science University, Portland, OR; 22-28 g, 5-6/group). Gene expression of CRF in the proximal colon and hypothalamus (positive control) and proinflammatory markers (MCP-1, MIP-1α, IL-1β, TNF-α, iNos, Cox2), early growth response gene-1 (Egr-1), an important inflammatory transcription factor and antiinflammatory markers (IL-6, TGF-β) in the proximal colon were assessed using reverse transcription polymerase chain reaction (RT-PCR) and real time quantitative PCR. Results: CRF transcript was significantly elevated by 2.8 fold in hypothalamus and also in the proximal colon by 2.2 fold in CRF-OE mice compared to WT mice. The gene expression of proinflammatory markers and Egr-1 was significantly upregulated in the proximal colon of CRF-OE mice while antiinflammatory markers detected in this study were unchanged (table 1). Conclusion: These data show that the CRF gene is expressed and upregulated in the colon like in the hypothalamus in the CRF-OE mice and established new evidence that chronic stress promotes proinflammation in the mouse colon which may play an important proinflammatory role in IBS patients. (Supproted by NIH grand DK057238, DK41301). Table 1. CRF overexpression induces upregulation of proinflammatory markers in mice colon (% wild type (WT) mice; *p<0.05 vs WT mice)