Summary Polymorphisms of IL-1β are associated with an increased risk of solid malignancies. Here, we show that stomach-specific expression of human IL-1β in transgenic mice leads to spontaneous gastric inflammation and cancer that correlates with early recruitment of myeloid-derived suppressor cells (MDSCs) to the stomach. IL-1β activates MDSC in vitro and in vivo through an IL-1RI/NF-κB pathway. IL-1β transgenic mice deficient in T and B lymphocytes develop gastric dysplasia accompanied by a marked increase in MDSCs in the stomach. Antagonism of IL-1 receptor signaling inhibited the development of gastric preneoplasia and suppressed MDSC mobilization. These results demonstrate that pathologic elevation of a single proinflammatory cytokine may be sufficient to induce neoplasia and provide a direct link between IL-1β, MDSCs and carcinogenesis.

Chronic inflammation increases cancer risk. While it is clear that cell signaling elicited by inflammatory cytokines promotes tumor development, the impact of DNA damage production resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) on tumor development has not been directly tested. RONS induce DNA damage that can be recognized by alkyladenine DNA glycosylase (Aag) to initiate base excision repair. Using a mouse model of episodic inflammatory bowel disease by repeated administration of dextran sulfate sodium in the drinking water, we show that Aag-mediated DNA repair prevents colonic epithelial damage and reduces the severity of dextran sulfate sodium-induced colon tumorigenesis. Importantly, DNA base lesions expected to be induced by RONS and recognized by Aag accumulated to higher levels in Aag-deficient animals following stimulation of colonic inflammation. Finally, as a test of the generality of this effect we show that Aag-deficient animals display more severe gastric lesions that are precursors of gastric cancer after chronic infection with Helicobacter pylori. These data demonstrate that the repair of DNA lesions formed by RONS during chronic inflammation is important for protection against colon carcinogenesis.

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Helicobacter pylori infection results in chronic gastritis, which may progress to gastric cancer. In this study, we investigated the efficacy of H. pylori eradication in preventing the progression of gastritis to gastric cancer in H. pylori-infected transgenic INS-GAS mice. H. pylori infection induced severe dysplasia and gastric cancer classified as high-grade and lowgrade gastrointestinal intraepithelial neoplasia (GIN) in INS-GAS mice at 28 weeks postinfection (WPI). H. pylori eradication therapy using omeprazole, metronidazole, and clarithromycin was administered p.o. at 8, 12, or 22 WPI. Compared with untreated infected mice, H. pylori eradication at 8, 12, and 22 WPI significantly reduced the severity of dysplasia (P < 0.01). Moreover, H. pylori eradication at 8 WPI completely prevented the development of GIN (P < 0.001).Although not as effective as early antimicrobial treatment, prevention of progression to high-grade GIN was achieved by H. pylori eradication at 12 and 22 WPI (P < 0.05). Consistent with reduced gastric pathology, H. pylori eradication at all time points significantly down-regulated gastric Interferon-;, tumor necrosis factor-A, inducible nitric oxide synthase, and Reg 1 mRNA levels (P < 0.05) and reduced epithelial proliferation in the corpus (P < 0.01) compared with untreated infected mice. We concluded that H. pylori eradication prevented gastric cancer to the greatest extent when antibiotics are given at an early point of infection, but that eradication therapy given at a later time point delayed the development of severe dysplastic lesions. [Cancer Res 2008;68(9):3540-8]

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Focal cerebral ischemia and traumatic brain injury induce an escalating amount of cell death because of harmful mediators diffusing from the original lesion site. Evidence suggests that healthy cells surrounding these lesions attempt to protect themselves by producing endocannabinoids (eCBs) and activating cannabinoid receptors, the molecular target for marijuana-derived compounds. Indeed, activation of cannabinoid receptors reduces the production and diffusion of harmful mediators. Here, we provide evidence that an exception to this pattern is found in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. We show that cell damage induced by EAE does not lead to increase in eCBs, even though cannabinoid receptors are functional because synthetic cannabinoid agonists are known to confine EAE-induced lesions. This lack of eCB increase is likely due to IFN-␥, which is released by primed T cells invading the CNS. We show that IFN-␥ disrupts the functionality of purinergic P2X7 receptors, a key step controlling eCB production by microglia, the main source of eCBs in brain. Accordingly, induction of EAE in P2X 7 ؊/؊ mice results in even lower eCB levels and more pronounced cell damage than in wild-type mice. Our data suggest that the high level of CNS IFN-␥ associated with EAE disrupts eCBmediated neuroprotection while maintaining functional cannabinoid receptors, thus providing additional support for the use of cannabinoid-based medicine to treat multiple sclerosis.cannabinoid ͉ microglia ͉ purinergic ͉ multiple sclerosis P hysiological stimuli and pathological conditions lead to differential increases in brain endocannabinoids (eCBs) that regulate distinct biological functions. Physiological stimuli lead to rapid and transient (seconds to minutes) increases in eCBs that activate neuronal CB 1 receptors, modulate ion channels, and inhibit neurotransmission (1), whereas pathological conditions lead to much slower and sustained (hours to days) increases in the eCB tone that change gene expression, implementing molecular mechanisms that prevent the production and diffusion of harmful mediators (2-9). Specifically, increases in the eCB tone activate immune CB 2 receptors, which reduce the expression of proinflammatory cytokines and enzymes involved in the generation of free radicals, and neuronal CB 1 receptors, thereby increasing the expression of growth factors. Although we are starting to understand how sustained increases in eCB tone and corresponding activation of cannabinoid receptors implement a protective mechanism to confine lesions, we still lack essential information on the molecular mechanism controlling the brain's eCB tone. ResultsNeuropathologies of different etiologies are all associated with increases in eCB tone (2,3,8,10,11), suggesting that cell damage itself may initiate this response. In previous studies, we showed that activation of purinergic P2X 7 receptors increases the production of the most abundant eCB, 2-arachidonoylglycerol (2-AG), from microglia and that the...

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