This is in contrast to IL-10?/?NOD?/? mice in which only 6 of 20 (30%) mice had developed colitis (Fig. 1A). At 18 wk of age, the reduction in the incidence of colitis in IL-10?/?NOD2?/? mice was associated with significant reduction in serum amyloid A, EMD 1214063 a nonspecific marker of inflammation (Fig. 1B). FIGURE 1. Chronic colitis is ameliorated in IL-10?/?NOD2?/? mice. The development of colitis was investigated in IL-10?/? and IL-10?/?NOD2?/? mice. (A) The incidence of clinical colitis … IBD and colitis in IL-10?/? mice are characterized by increased mucosal inflammatory cytokine levels arising primarily from the immune cell infiltrate. At 6 wk of age, there was no significant difference in colonic cytokine levels in IL-10?/? mice compared with IL-10?/?NOD2?/? mice.
However, by 10 wk of age, levels of IL-12p70, TNF-��, and IL-1�� were significantly elevated in the colons of IL-10?/? mice when compared with IL-10?/?NOD2?/? mice of the same age. Moreover, proinflammatory colonic cytokine levels remained attenuated in older (18-wk) IL-10?/?NOD2?/? mice, thus confirming amelioration of spontaneous colitis (Fig. 1D). To look specifically at progression of intestinal inflammation, we analyzed the colon for histopathological changes in 6-, 10-, and 18-wk-old mice. At 6 wk of age, histological analysis revealed a small inflammatory cell infiltrate restricted to the lamina propria at the base of the crypts and elongated crypts (mild damage) in a small number of IL-10?/? mice (3 of 11) and IL-10?/?NOD2?/? mice (1 of 11).
However, there was no significant difference in histopathology between IL-10?/? and IL-10?/?NOD2?/? at 6 wk of age (Fig. 1C), concurring with the slight, but nonsignificant, increase in colon cytokines observed in IL-10?/? mice compared with IL-10?/?NOD2?/? mice (Fig. 1D). By 10 wk of age, the incidence (11 of 12) and severity of histopathology had increased in IL-10?/? mice, characterized by increased inflammatory cell infiltrate and crypt elongation associated with goblet cell depletion along the length of the colon (Fig. 1E, ,1F).1F). In contrast, 5 of 11 IL-10?/?NOD2?/? mice had no histopathology, and those that did had limited inflammation and epithelial damage, resulting in significantly less histopathology scores (Fig. 1C). At 18 wk, IL-10?/? mice had marked mucosal thickening, epithelial hyperplasia, and crypt abscesses involving distal and proximal colon (Fig.
1E, ,1F).1F). Severe epithelial damage was associated with increased immune infiltrate extending into the submucosa and the presence of immune cell foci. This is in contrast to colons from 18-wk-old IL-10?/?NOD2?/? mice that had significantly less mucosal damage and immune cell infiltrate. Taken together these data demonstrate that deletion of NOD2 in IL-10?/? mice AV-951 ameliorates spontaneous chronic colitis.