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


OBJECTIVE
We evaluated the direct effect of angiotensin II (AII) on the pathogenesis of immune mediated colitis using angiotensinogen deficient homozygous (Atg-/-) mice.


METHODS
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)-1beta, interferon gamma (IFN-gamma)) was impaired in Atg-/- mice. Furthermore, expression of cytokines such as IL-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-1beta, IFN-gamma). 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.
Inokuchi
Y
Y
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine and School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan. inokuchi@kd5.so-net.ne.jp
Morohashi
T
T
Kawana
I
I
Nagashima
Y
Y
Kihara
M
M
Umemura
S
S
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000808:Angiotensinogen / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D018928:Immunity, Mucosal; D007413:Intestinal Mucosa / Q000276:immunology; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D012084:Renin-Angiotensin System; D014302:Trinitrobenzenesulfonic Acid; D015431:Weight Loss / Q000187:drug effects / Q000235:genetics
D047228:Angiotensin II Type 1 Receptor Blockers; D016207:Cytokines; D000808:Angiotensinogen; D014302:Trinitrobenzenesulfonic Acid; D019808:Losartan