Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses.

Berg, Daniel J.; Davidson, N M; Kühn, Ralf; Müller, Werner; Menon, Satish; Holland, Gina; Thompson-Snipes, LuAnn; Leach, Michael W.; Rennick, Donna

doi:10.1172/jci118861

Cited by 1,043 publications

(972 citation statements)

References 41 publications

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“…In mouse IBD models, pro-inflammatory IFN-+ has a wellcharacterized role in macrophage activation [38]; on the other hand, IL-10 reduces macrophage secretion of inflammatory mediators by inhibiting NF-‹ B activation [39]. Furthermore, IL-10-deficient mice show enhanced production of colonic pro-inflammatory cytokines, including IFN-+ , and develop spontaneous chronic enterocolitis [40]. Based on our results, we speculate that the lack of IFN-+ response and the increased IL-10 levels observed in CCR6-deficient mice, both before and in the first days of DSS treatment, may reduce the inflammatory function of macrophages and aid in attenuating colon damage in these animals.…”

Section: Discussionmentioning

confidence: 99%

CCR6 has a non‐redundant role in the development of inflammatory bowel disease

et al. 2003

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Antigen-loaded tissues such as the intestinal mucosa must simultaneously elicit appropriate immune response to innocuous bacteria and food proteins, and to potentially harmful antigens. Impairment of the mechanisms controlling this response may mediate the excessive immune reaction that can lead to tissue destruction and inflammatory intestinal diseases, including inflammatory bowel disease. The intestinal epithelium influences local immune responses through the expression of adhesion molecules, costimulatory factors, cytokines and chemokines. CCL20, a g -chemokine expressed in epithelia from colon and other intestinal tissue, plays a role in immune responses of intestinal mucosa, as deduced from the defects in intestinal leukocyte homeostasis shown by mice lacking CCR6, the CCL20 receptor. We studied the response of CCR6-deficient mice in two models of inflammatory bowel disease. The data show that absence of CCR6 resulted in less severe intestinal pathology in animals treated with dextran sodium sulfate. Conversely, CCR6 deficiency alters leukocyte homeostasis and the cytokine environment in the intestinal mucosa; these changes are sufficient to confer susceptibility to trinitrobenzene sulfonic acid-induced intestinal inflammation in the otherwise resistant C57BL/6J mouse strain. These results suggest that the CCR6/ CCL20 axis has a critical, non-redundant role in the in vivo control of immune responses in the intestine.

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Section: Discussionmentioning

confidence: 99%

CCR6 has a non‐redundant role in the development of inflammatory bowel disease

et al. 2003

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“…Formalin-fixed tissues were embedded in paraffin, cut at 5 m, and stained with H&E. Colonic lesions were scored, by a comparative pathologist blinded to sample identity, using criteria previously described, on a 0 -4 ascending scale (26,27). Criteria assessed included mucosal/submucosal inflammation, transmural and mesenteric perivasculitis, hyperplasia, and dysplasia.…”

Section: Histopathologic Evaluationmentioning

confidence: 99%

NF-κB Is Required Within the Innate Immune System to Inhibit Microflora-Induced Colitis and Expression of IL-12 p40

Tomczak

Erdman

Poutahidis

et al. 2003

The Journal of Immunology

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We have previously presented evidence demonstrating that mice deficient in NF-κB subunits are susceptible to colitis induced by the pathogenic enterohepatic Helicobacter species, H. hepaticus. However, it has not been determined whether NF-κB is required within inhibitory lymphocyte populations, within cells of the innate immune system, or both, to suppress inflammation. To examine these issues, we have performed a series of adoptive transfer experiments using recombination-activating gene (Rag)-2−/− or p50−/−p65+/−Rag-2−/− mice as hosts for wild-type (WT) and p50−/−p65+/− lymphocyte populations. We have shown that although the ability of H. hepaticus to induce colitis in Rag-2−/− mice is inhibited by the presence of either WT or p50−/−p65+/− splenocytes, these splenocyte populations are unable to suppress H. hepaticus-induced colitis in p50−/−p65+/−Rag-2−/− mice. Colitis in these animals is characterized by increased expression of inflammatory cytokines including IL-12 p40, and depletion of IL-12 p40 from p50−/−p65+/− mice ameliorates H. hepaticus-induced disease. Consistent with a primary defect in the regulation of IL-12 expression, H. hepaticus induced markedly higher levels of IL-12 p40 in p50−/−p65+/− macrophages than in WT macrophages. These results suggest that inhibition of H. hepaticus-induced IL-12 p40 expression by NF-κB subunits is critical to preventing colonic inflammation in response to inflammatory microflora.

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“…1,2 The activity of IL-10 in counter regulating mucosal inflammation is likely to be multifactorial. IL-10 is a potent down regulator of IL-12 production and thus acts at the level of Th1 cell induction.…”

Section: Introductionmentioning

confidence: 99%

“…These studies have shown that systemic IL-10 administration is able to prevent intestinal inflammation by down regulating the intestinal pro-inflammatory Th1 response. 1,9,10 Based on these successful experimental findings, recombinant (r)IL-10 was administered by subcutaneous injection to patients with either mild/moderate or steroid refractory Crohn's disease, as well as in patients undergoing ileal resection to prevent postoperative recurrence. [11][12][13] Although the data indicated that systemic rIL-10 therapy is safe and well tolerated, this therapy resulted in only a modest response in steroid naïve patients, and no significant benefit compared to placebo in steroid refractory patients.…”

Section: Introductionmentioning

confidence: 99%