Amelioration of 2,4,6-trinitrobenzene sulphonic acid induced colitis in angiotensinogen gene knockout mice

Inokuchi, Y.; Morohcashi, T.; Kawana, I.; Nagashima, Y.; Kihora, M.; Umemura, S.
March 2005
Gut;Mar2005, Vol. 54 Issue 3, p349
Academic Journal
Background: A number of recent studies have demonstrated a protective effect of renin-angiotensin system (RAS) antagonism against immune mediated diseases such as myocarditis, chronic allograft rejection, and antiglomerular basement membrane nephritis. To our knowledge, there has been no report on the immunological contribution of the RAS in colonic tissue. Aims: We evaluated the direct effect of angiotensin II (All) on the pathogenesis of immune mediated colitis using angiotensinogen deficient homozygous (Atg-/-) mice. Subjects: 2,4,6-Trinitrobenzene sulphonic acid (TNBS) colitis was induced in Atg-/- and wild-type (Atg+/+) mice. Methods: Levels of proinflammatory cytokines in the colon were determined by enzyme linked immunosorbent assay. Histological analysis was performed simultaneously. Results: Although Atg-/- mice developed colitis, the degree was much milder than that in Atg+/+ mice (p<0.05). Colonic cytokine analysis showed that the production of proinflammatory cytokines (interleukin (IL)-1 β, interferon γ (IFN-γ)) was impaired in Atg-/- mice. Furthermore, expression of cytokines such as lL-4 and IL-10 in the colon was predominant in Atg-/-- compared with Atg+/+ mice after TNBS instillation (p<0.005, p<0.01, respectively). Similarly, subcutaneous infusion of losartan suppressed colitis (p<0.05) and the production of proinflammatory cytokines (IL-1 β, IFN-γ). These results indicate that the RAS is directly involved in the pathogenesis of TNBS colitis through regulation of proinflammatory and anti-inflammatory cytokines in the colon. Conclusions: This study revealed that the RAS is involved in the immune system in the colon. Antagonism of the RAS is a potential prophylactic strategy for the treatment of human inflammatory bowel disease.


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