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Dynamic interaction with the immune system profoundly regulates tumor cell dormancy. However, it is unclear how immunological cues trigger cancer cell-intrinsic signaling pathways for entering into dormancy. Here, we show that IFN-[beta] treatment induced tumor-repopulating cells (TRC) to enter dormancy through an indolamine 2,3-dioxygenase/kynurenine/ aryl hydrocarbon receptor/p27-dependent (IDO/Kyn/AhR/p27-dependent) pathway. Strategies to block this metabolic circuitry did not relieve dormancy, but led to apoptosis of dormant TRCs in murine and human melanoma models. Specifically, blocking AhR redirected IFN-[beta] signaling to STAT3 phosphorylation through both tyrosine and serine sites, which subsequently facilitated STAT3 nuclear translocation and subsequent binding to the p53 promoter in the nucleus. Upregulation of p53 in turn disrupted the pentose phosphate pathway, leading to excessive ROS production and dormant TRC death. Additionally, in melanoma patients, high expression of IFN-[beta] correlated with tumor cell dormancy. Identification of this mechanism for controlling TRC dormancy by IFN-[beta] provides deeper insights into cancer-immune interaction and potential new cancer immunotherapeutic modalities., Introduction Various types of viruses are capable of infecting the host, causing viral persistence, latency, and host tumorigenesis, typically including liver, cervical, and nasopharyngeal cancers and some subtypes of leukemia. [...]

Lactobacillus reuteri (L. reuteri) is a probiotic that inhibits the severity of enteric infections and modulates the immune system. Human-derived L. reuteri strains DSM17938, ATCC PTA4659, ATCC PTA 5289, and ATCC PTA 6475 have demonstrated strain-specific immunomodulation in cultured monocytoid cells, but information about how these strains affect inflammation in intestinal epithelium is limited. We determined the effects of the four different L. reuteri strains on lipopolysaccharide (LPS)-induced inflammation in small intestinal epithelial cells and in the ileum of newborn rats. IPEC-J2 cells (derived from the jejunal epithelium of a neonatal piglet) and IEC-6 cells (derived from the rat crypt) were treated with L. reuteri. Newborn rat pups were gavaged cow milk formula supplemented with L. reuteri strains in the presence or absence of LPS. Protein and mRNA levels of cytokines and histological changes were measured. We demonstrate that even though one L. reuteri strain (DSM 17938) did not inhibit LPS-induced IL-8 production in cultured intestinal cells, all strains significantly reduced intestinal mucosal levels of KC/GRO (~IL-8) and IFN-[gamma] when newborn rat pups were fed formula containing LPS [+ or -] L. reuteri. Intestinal histological damage produced by LPS plus cow milk formula was also significantly reduced by all four strains. Cow milk formula feeding (without LPS) produced mild gut inflammation, evidenced by elevated mucosal IFN-[gamma] and IL-13 levels, a process that could be suppressed by strain 17938. Other cytokines and chemokines were variably affected by the different strains, and there was no toxic effect of L. reuteri on intestinal cells or mucosa. In conclusion, L. reuteri strains differentially modulate LPS-induced inflammation. Probiotic interactions with both epithelial and nonepithelial cells in vivo must be instrumental in modulating intrinsic anti-inflammatory effects in the intestine. We suggest that the terms anti- and proinflammatory be used only to describe the effects of a probiotic in the living host. formula; intestine; cytokine; endotoxin; probiotic doi: 10.1152/ajpgi.00124.2010.

Liu Y, Biedsoe G, Hagiwara M, Yang Z, Shen B, Chao L, Chan J. Blockade of endogenous tissue kallikrein aggravates renal injury by enhancing oxidative stress and inhibiting matrix degradation. Am J Physiol Renal Physiol 298: FI033-F1040, 2010. First published January 20, 2010; doi: 10.1152/ajprenal.00518.2009.--Levels of tissue kallikrein (TK) are significantly lower in the urine of patients with kidney failure, and TK expression is specifically diminished in rat kidney after recovery from ischemia-reperfusion injury. In this study, we investigated the functional consequence of blocking endogenous TK activity in a rat model of chronic kidney disease. Inhibition of endogenous TK levels for 10 days by neutralizing TK antibody injection in DOCA-salt rats caused a significant increase in blood urea nitrogen and urinary protein levels, and a decrease in creatinine clearance. Kidney sections from anti-TK antibody-treated rats displayed a marked rise in tubular dilation and protein cast accumulation as well as glomerular sclerosis and size. TK blockade also increased inflammatory cell infiltration, myofibroblast and collagen accumulation, and collagen fraction volume. Elevated renal inflammation and fibrosis by anti-TK antibody were associated with increased expression of tumor necrosis factor-[alpha], intercellular adhesion molecule-l, tissue inhibitor of metalloproteinase-2 (TIMP-2), and plasminogen activator inhibitor-1 (PAI-I). Moreover, the detrimental effect of TK blockade resulted in reduced nitric oxide (NO) levels as well as increased serum lipid peroxidation, renal NADH oxidase activity, and superoxide formation. In cultured proximal tubular ceils, TK inhibited angiotensin II-induced superoxide production and NADH oxidase activity via NO formation. In addition, TK markedly increased matrix metalloproteinase-2 activity with a parallel reduction of TIMP-2 and PAI-I synthesis. These findings indicate that endogenous TK has the propensity to preserve kidney structure and function in rats with chronic renal disease by inhibiting oxidative stress and activating matrix degradation pathways. chronic kidney disease; inflammation; fibrosis doi: 10.1152/ajprenal.00518.2009.

It is unclear whether the broad inflammatory response shown in neonatal necrotizing enterocolitis (NEC) is the cause or the effect of tissue injury. Toll-like receptors (TLRs) on intestinal dendritic, mononuclear, and epithelial cells recognize bacterial ligands and damaged tissues, thus activating the inflammatory response. The present study aimed to determine whether active TLR signaling would precede histological injury in NEC. Newborn rat pups were divided into four groups: dam fed, dam fed-hypoxic, formula fed, and formula fed-hypoxic (NEC). The ileal tissues were evaluated for NEC scores at 24, 48, 72, and 120 h. Quantitative real-time reverse transcription-polymerase chain reaction and immunohistochemistry were used to measure and localize intestinal TLRs. Cytokines were assessed by a multispot cytokine array. Among the four groups, ileal injury was seen only after 72 h of formula feeding and hypoxia. We found selective induction of mRNA levels in NEC compared with dam-fed controls for TLR2 > TLR4 > TLR1 = TLR3, TLR7, and TLR9 > TLR6 (P < 0.01); TLR5 was downregulated (P < 0.01). All TLR changes started at 48 h, before any histological evidence of NEC. Both Th1-type cytokines (IFN-[gamma], IL-1 [beta], TNF-[alpha], and KC/GRO) and Th2-type cytokines (IL-4, IL-5 and IL-13) were significantly increased in NEC but also in nondamaged formula-fed rat ileum. In conclusion, the intestinal expression of TLRs and cytokines precedes histological injury in the experimental NEC. prematurity; hypoxia; breast milk; formula; inflammation

In intestinal cells, arginine (Arg) is 1 of the 2 most potent amino acid activators of [p70.sup.s6k], a key regulator of 5'-terminal oligopyrimidine mRNA translation, a necessary condition for increased cell migration. To investigate the mechanism of response to Arg, we used the rat crypt cell line cdx2-transformed IEC-6 cells (cdx2-IEC) and measured cell migration, immunocytochemical analysis of [p70.sup.s6k] activation in response to Arg, and production of nitric oxide (NO). When treated with Arg, cdx2-IEC increased in phosphorylation on Thr-389 of [p70.sup.s6k] ([pp70.sup.s6k]) compared with control (P < 0.01). Phospho-Thr-421/Ser-424-[p70.sup.s6k] was located in the nucleus shortly after Arg treatment. Arg enhanced [pp70.sup.s6k], cell migration (55% wound coverage), and NO production. In comparison, the branched-chain amino acid leucine (Leu) activated [pp70.sup.s6k], was a weaker stimulator of migration (23% coverage), and did not increase NO. A total of 25 [micro]mol/L DETA-NONOate (DETA/NO) did not significantly enhance phosphorylation of [p70.sup.s6k] but enhanced the rate of cell migration by ~25%. Wound coverage with Leu plus DETA/NO (25 [mu]mol/L) was greater than coverage with DETA/NO alone (P < 0.01). These and our previous studies lead to a model in which Arg must stimulate both [pp70.sup.s6k] (in the nucleus) and NO release to enhance intestinal epithelial cell migration, which may be relevant to diseases that involve intestinal villous injury.