Background In atopic individuals, food ingestion drives the production of IgE antibodies that can trigger hypersensitivity reactions. The IL-4 pathway plays critical roles in this response and genetic polymorphisms in its components have been linked to allergy. Objective To test whether an activating mutation in the IL-4 receptor (IL-4R) α chain enhances allergic responses to a food antigen. Methods F709 mice, in which the IL-4Rα immuno-tyrosine inhibitory motif (ITIM) motif is inactivated, were gavage fed with ovalbumin (OVA). Reactions to OVA challenge and immune responses including antibody production and Th2 responses were assessed. Results F709 mice, but not wild-type (WT) controls, sensitized by gavage with OVA and either cholera toxin (CT) or Staphylococcal enterotoxin B (SEB), displayed mast cell activation and systemic anaphylaxis upon enteral challenge. Anaphylaxis was elicited even in F709 mice enterally sensitized with OVA alone. Bone marrow chimera experiments established that the increased sensitivity conferred by the F709 genotype was mediated mostly by hematopoietic cells but that nonhematopoietic cells also contributed. F709 mice exhibited increased intestinal permeability to macromolecules. The F709 genotype conferred increased OVA-specific IgE but not IgG1 responses, local and systemic Th2 responses and intestinal mast cell hyperplasia as compared with WT mice. Anaphylaxis was abrogated in F709 mice lacking IgE or the high affinity receptor for IgE (FcεRI). Conclusion Augmented IL-4Rα signaling confers increased intestinal permeability and dramatically enhanced sensitivity to food allergens. Unlike anaphylaxis to injected antigens, which in rodents can be mediated by either IgE or IgG antibodies, the food-induced response in F709 mice is solely IgE-dependent.

Pituitary adenylyl cyclase activating peptide (PACAP) is expressed in central, sensory, autonomic, and enteric neurons. Although it classically acts as a neurotransmitter/neuromodulator, recent studies indicate that PACAP can also regulate immune function. To this effect, PACAP has been shown to reduce clinical symptoms and inflammation in mouse models of human immunebased diseases such as rheumatoid arthritis, Crohn's Disease, septic shock and multiple sclerosis. Despite these findings, the role of the endogenous peptide in regulating immune function is unknown. To determine if endogenous PACAP plays a protective role in inflammatory bowel disease (IBD) and IBD-associated colorectal cancer in mice, PACAP-deficient (KO) mice were subjected to 3 cycles of dextran sulfate sodium (DSS) in drinking water over 2 months, an established mouse model for colitis. Compared to wild type (WT) controls, PACAP KO mice exhibited more severe clinical symptoms of colitis and had significantly higher colonic inflammation on pathological examination. Moreover, 60% of the PACAP KO mice developed colorectal tumors with an aggressive-appearing pathology. Consistent with published data, DSS-treated WT mice did not develop such tumors. The results demonstrate a new mouse model which rapidly develops inflammation-associated colorectal cancer in the absence of a carcinogen. ' 2007 Wiley-Liss, Inc.Key words: pituitary adenylyl cyclase activating peptide (PACAP); inflammation; colorectal cancer; colitis; cancer Chronic inflammatory diseases are known to be linked to the development of cancer.1 In one of the more prominent examples, colorectal cancer (CRC) occurs at a significantly higher rate in patients with inflammatory bowel disease (IBD) compared to the normal population. The increased incidence of CRC in IBD patients appears to be most pronounced in individuals with extensive and long-term ulcerative colitis.2 The rate of CRC begins to increase significantly after 10 years of colitis, with a cumulative probability of 18% after 30-year duration. Like its more common counterpart, sporadic CRC, the prognosis for IBD-associated CRC is poor: the 5-year survival rate is about 50%. Preventative treatment includes colectomy and the use of drugs. Retrospective studies suggest that chronic treatment with 5-aminosalicylic acid or related drugs can reduce the incidence of CRC in patients with IBD, although the studies are not conclusive, and the mechanism of drug action is uncertain. COX-2 inhibitors may also provide protection and appear to have less potential to aggravate IBD than other nonsteroidal antiinflammatory drugs. Despite potential preventative measures in these patients, the incidence of CRC remains high, and new therapeutic modalities must be explored. Moreover, improved animal models are needed to better understand the disease, to test new treatments, and to understand the mechanisms of action of various treatments. In this regard, several rodent models have been developed to study the pathogenesis of chronic ulcerative colitis and...

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Hydroferrate fluid, MRN-100, an iron-based compound derived from bivalent and trivalent ferrates, is a potent antioxidant compound. Therefore, we examined the protective effect of MRN-100 against γ-radiation-induced lethality and damage to hematopoietic tissues in fish. A total of 216 Nile tilapia fish (Oreochromis niloticus) were randomly divided into four groups. Group 1 served as a control that was administered no radiation and no MRN-100 treatment. Group 2 was exposed only to γ-radiation (15 Gy). Groups 3 and 4 were pre-treated with MRN-100 at doses of either 1 ml/l or 3 ml/l in water for 1 week, and subsequently exposed to radiation while continuing to receive MRN-100 for 27 days. The survival rate was measured, and biochemical and histopathological analyses of hematopoietic tissues were performed for the different treatment groups at 1 and 4 weeks post-radiation. Exposure to radiation reduced the survival rate to 27.7%, while treatment with MRN-100 maintained the survival rate at 87.2%. In addition, fish exposed to γ-radiation for 1 week showed a significant decrease in the total number of white blood cells (WBCs) and red blood cells (RBCs) series. However, treatment with MRN-100 protected the total WBC count and the RBCs series when compared with irradiated fish. Furthermore, significant histological lesions were observed in the hepatopancreas, spleen and gills of irradiated fish. However, treatment with MRN-100 protected the histopathology of various organs. We conclude that MRN-100 is a radioprotective agent in fish and may be useful as an adjuvant treatment to counteract the adverse side effects associated with radiation exposure.