Dietary melatonin and liver cancer incidence in Japan: From the Takayama study.

There is some biological plausibility that exogenous melatonin plays a role in preventing liver carcinogenesis. There has been little research on the association between melatonin intake in a normal diet and health outcomes. We evaluated the association between dietary melatonin intake and the incidence of liver cancer in a population-based prospective study in Japan. This study included 30,824 residents of Takayama city who were 35 years of age or older in 1992 and had participated in the Takayama study, Japan. Dietary intake was assessed using a validated food frequency questionnaire at the baseline. Melatonin content in foods was measured by liquid chromatography-tandem mass spectrometry. Cancer incidence was confirmed through regional population-based cancer registries in Gifu. Liver cancer was defined as code C22 according to the International Classification of Diseases and Related Health Problems, 10th Revision. Hazard ratios for liver cancer were estimated for the tertile groups of melatonin intake using a Cox proportional hazards model. During the mean follow-up period of 13.6 years, 189 individuals developed liver cancer. Compared with subjects in the lowest tertile of melatonin intake, those in the middle and highest tertiles had decreased risks of liver cancer, with a significant linear trend after multivariate adjustments (hazard ratios: 0.64 and 0.65, respectively, trend p = 0.023). There was no significant interaction by sex (interaction p = 0.54). This initial finding, which needs to be confirmed by further studies, suggests that consuming melatonin-containing foods might play a role in the prevention of liver cancer.

Dietary advanced glycation end products and cancer risk in Japan: From the Takayama study.

Few large epidemiological studies have evaluated the association between dietary advanced glycation end products (AGEs) and cancer risk. We evaluated the relationship between dietary AGE intake and the incidence of total cancer and site-specific cancers in a population-based prospective study in Japan. Participants were 14,173 men and 16,549 women who were 35 years of age or older in 1992. Dietary intake was assessed via a validated food frequency questionnaire. Intake of the AGE Nε -carboxymethyl-lysine (CML) was estimated using databases of CML content in foods determined using ultraperformance liquid chromatography-tandem mass spectrometry. Cancer incidence was confirmed through regional population-based cancer registries. During a mean follow-up period of 13.3 years, 1954 men and 1477 women developed cancer. We did not observe a significant association between CML intake and the risk of total cancer in men or women. In men, compared with the lowest quartile of CML intake, the hazard ratios of liver cancer for the second, third, and highest quartiles were 1.69 (95% CI: 0.92-3.10), 1.48 (95% CI: 0.77-2.84), and 2.10 (95% CI: 1.10-3.98; trend p = 0.04). Conversely, a decreased relative risk of male stomach cancer was observed for the second and highest quartiles of CML intake versus the lowest quartile, with hazard ratios of 0.73 and 0.67, respectively (trend p = 0.08). Our finding on the potential harmfulness of consuming AGEs on liver cancer risk is intriguing and warrants further study.

Activation of NLRP3 signalling accelerates skin wound healing.

The process of skin wound healing involves the following three steps: inflammation, tissue formation and tissue remodelling. These optimal steps are required for the development of normal wound healing. Recent reports demonstrated that inflammasomes are involved in the innate immune response. In the present study, we examined whether the activation of inflammasomes affects the process of skin wound repair. The skin wound repair model was established using wild-type (WT), NACHT, LRR and PYD domains-containing protein 3 (NALP3) knockout (KO) and ASC-KO mice. The wounds were observed every other day, and changes in wound size over time were calculated using photography. Wound repair in NALP3-KO and ASC-KO mice was significantly impaired compared with WT mice. Isoliquiritigenin, an inhibitor of NALP3, decreased the rate of wound repair in WT mice. mRNA expression of pro-inflammatory cytokines in the wound sites of NALP3-KO mice was markedly decreased compared with WT mice. Treatment with adenosine triphosphate (ATP), a ligand of NALP3, upregulated the mRNA expression of pro-inflammatory cytokines at the wound site and accelerated wound healing in the WT mice. Scratch assay revealed that ATP accelerated wound closure in mouse embryonic fibroblasts from WT mice but not from NALP3-KO mice. In conclusion, the present study demonstrated that NALP3 pathway activation is involved in wound repair, and the topical use of ATP may be useful as an effective treatment for accelerating wound healing.

The inhibition of NLRP3 signaling attenuates liver injury in an α-galactosylceramide-induced hepatitis model.

Inflammasomes are involved in innate immune responses. Several NOD-Like receptors (NLRs) participate in the formation of inflammasomes. NACHT, LRR and PYD domains-containing protein 3 (NALP3) belongs to the NLR family and recognizes adenosine triphosphate (ATP), crystals, and Reactive Oxygen Species (ROS). This study examined the effect of inflammasomes on alpha-galactosylceramide (GalCer)-induced liver injury using NALP3-knockout (KO) mice. GalCer administration induced inflammasome activation and IL-1ß-maturation. In NALP3-KO mice treated with GalCer, serum ALT levels were significantly reduced compared with those in GalCer-treated WT mice. Histological examination revealed decreased necrosis in NALP3-KO mice compared with WT mice, consistent with ALT levels. Expression of proinflammatory cytokines (such as IL-6, and TNF-α) and chemokines was also significantly suppressed in NALP3-KO mice. Moreover, flow cytometry analysis revealed fewer infiltrating immune cells in the livers of GalCer-treated NALP3-KO mice. Inportantly, the frequency of MDSCs (CD11b+Gr-1int cells), which suppress the immune response, was significantly increased in GalCer-treated NALP3-KO mice. In conclusion, NALP3 inhibition attenuated liver injury in GalCer-induced hepatitis. The inhibition of NALP3 signaling coused be a therapeutic target in immune-mediated liver injury.

Serum concentrations of l-kynurenine predict clinical outcomes of patients with peripheral T-cell lymphoma, not otherwise specified.

Indoleamine 2,3-dioxygenase exerts intense immunomodulatory effects due to enzymatic activities that catalyze the breakdown of the essential amino acid l-tryptophan. The activity of indoleamine 2,3-dioxygenase can be estimated by measuring serum l-kynurenine concentrations. Here, we aimed to determine the role of l-kynurenine as a prognostic factor for peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in a retrospective analysis of data derived from 31 consecutive patients between June 2000 and March 2013 who were histologically diagnosed with PTCL-NOS according to the World Health Organization classification and treated with 6-8 cycles of cyclophosphamide, doxorubicin or pirarubicin, vincristine, and prednisolone. l-kynurenine concentrations in serum samples collected at admission were measured using high-performance liquid chromatography. The median serum concentration of l-kynurenine was 3.28 (range 0.92-8.16) µM. The l-kynurenine cutoff was set at 3.07 µM using receiver operating characteristics curves. The complete remission rates of patients with l-kynurenine <3.07 and ≥3.07 µM were 69% and 51%, respectively. The 5-year overall survival (OS) rates for patients with l-kynurenine <3.07 and ≥3.07 µM were 80.2% and 23.4%, respectively (p < 0.001). More advanced age, poor performance status, elevated lactate dehydrogenase, an unfavorable International Prognostic Index, and a poor prognostic index for T-cell lymphoma were significantly worse factors for OS. Multivariate analyses revealed only l-kynurenine as an independent prognostic factor for OS. In conclusion, serum concentrations of l-kynurenine might comprise a novel prognostic factor with which to determine the outcomes of treatment for PTCL-NOS. Copyright © 2016 John Wiley & Sons, Ltd.

The Inhibition of Indoleamine 2,3-Dioxygenase Accelerates Early Liver Regeneration in Mice After Partial Hepatectomy.

BACKGROUND AND AIM: The inflammatory response accelerates early liver regeneration after liver injury and resection. Recent studies have demonstrated that indoleamine 2,3-dioxygenase-1 (IDO1) suppresses the activation of inflammatory cells and induces immune tolerance. In this study, we examined the role of IDO1 in liver regeneration after partial hepatectomy (PHx). METHODS: WT or IDO1-knockout (IDO1-KO) mice received 70% PHx. The liver-body weight ratio after PHx was measured and hepatocyte growth was assessed by immunostaining. The expression of cell cycle genes and pro-inflammatory cytokines in the liver was analyzed by quantitative RT-PCR. In addition, 1-methyl-DL-tryptophan (1-MT), which is an IDO1 inhibitory agent, was given to WT mice and the liver-body weight ratio was measured after PHx. RESULTS: The liver-body weight ratio was significantly increased in IDO1-KO mice compared with that in WT mice after PHx. More Ki-67-positive cells were present in IDO1-KO mice than in WT mice after PHx. The expression of cell cycle genes (cyclin D1, cyclin E) and pro-inflammatory cytokines (IL-1ß, TNF-α and IL-6) was up-regulated in the remnant liver of IDO1-KO mice compared with WT mice. Moreover, treatment with 1-MT promoted liver regeneration. CONCLUSION: IDO1 deficiency promoted early liver regeneration after PHx, indicating that IDO1 suppresses the production of inflammatory cytokines and subsequently inhibits hepatocyte proliferation during liver regeneration.

Quantitative Sonographic Assessment of the Quadriceps Femoris Muscle in Healthy Japanese Adults.

OBJECTIVES: The aim of this study was to evaluate the relationships among aging, muscle strength, and image feature analysis of the quadriceps femoris muscle and to evaluate the relationship between aging, muscle strength, and sonographic findings. METHODS: One hundred forty-five healthy volunteers participated in the study. The participants were classified into 6 groups on the basis of sex and age. To assess muscle quality, texture analysis was defined with the following parameters: mean, skewness, kurtosis, inverse difference moment, sum of entropy, and angular second moment. The knee extension force in the sitting position and thickness of the quadriceps femoris muscle were also measured. RESULTS: The quadriceps femoris thickness, skewness, kurtosis, inverse difference moment, angular second moment, and muscle strength were significantly decreased in elderly participants versus those in the younger and middle-aged groups (P < .05). In contrast, the mean and sum of entropy were significantly decreased in the younger group compared with the middle-aged and elderly groups. CONCLUSIONS: Sonography has the capacity to quantitatively assess muscular morphologic changes due to aging and could be a valuable tool for early detection of musculoskeletal disorders.

Catechins and Its Role in Chronic Diseases.

The mechanisms of action of polyphenols have attracted much attention. Catechins are generally known as tea polyphenols. Researchers have extensively investigated the molecular mechanisms of these substances, especially (-)-epigallocatechin gallate of green tea catechin, and have provided new insights in the prevention and therapy for chronic diseases. This chapter summarizes catechins and their effects on chronic diseases, including metabolic syndromes, cardiovascular diseases, neurodegenerative diseases, and cancer, focusing on the effects of green tea catechins.

[Physiological Function of Apolipoproteins and Atherosclerosis].

We have studied the physiological function of four apolipoproteins. First, apo A-I is a major component of HDL and plays a crucial role in reverse cholesterol transport. The lipid-poor apo A-I concentration in plasma was significantly increased in patients with coronary artery disease compared with healthy controls, which may be caused by the impairment of the reverse cholesterol transport pathway. Second, the plasma A-IV concentration was significantly elevated in uremic patients, and we revealed the mechanism of apo A-IV accumulation in plasma using a rat model. Third, apo B48 is associated with lipid absorption in the intestinal epithelium, but the lymph apo B48 output was not changed during the absorption of mid-chain triglycerides, unlike apo A-IV. Fourth, we showed for the first time that the cerebrospinal apo E level was reduced in early-onset Alzheimer's disease and increased in a late-onset group. Taken together, apolipoproteins show various functions via the regulation of lipid metabolism. We have also studied the effect of cytokines on atherosclerosis using cytokine knockout mice. TNF-α and IL-1ß increased the number and size of atherosclerotic lesions, but IFN-γ attenuated the lesions. Plaque formation is influenced by not only the cholesterol level in plasma but also cytokine levels and other unknown factors. It may be of no merit to give cholesterol-lowering drugs to hypercholesterolemic patients without plaque. It is, thus, strongly expected that a biomarker which can predict the presence of plaque will be developed in the future.

[Introduction].

It is well-known that plasma HDL-C shows a negative correlation with the incidence of coronary artery disease, which was confirmed by the Framingham Study, a famous prospective cohort study, in 1977. At first, HDL-C was determined by the precipitation method, and then the homogeneous method of HDL-C determination was developed in the 1990's in Japan. This method enabled HDL-C measurement in a short time for many samples. HDL removes free cholesterol from somatic cells by accepting cell cholesterol via ATP-binding cassette transporter A1. Cholesterol ester in HDL is transferred to VLDL and LDL by the action of cholesterol ester transfer protein or is incorporated into the liver via SR-BI. This pathway is called reverse cholesterol transport, which can regress atheromatous plaques. On the other hand, some CETP inhibitors, which can increase the HDL-C level have been developed in the world. However, the development of all candidate drugs was stopped because of side or insufficient effects. In addition, patients with CETP deficiency, whose HDL-C levels are markedly high, sometimes show the findings of coronary artery disease. These observations indicate that elevating HDL-C levels alone may not lower the cardiovascular disease risk. Recently, it was reported that HDL has pleiotropic functions other than reverse cholesterol transport. Actually, HDL inhibits lipid oxidation, impairs leukocyte adhesion and monocyte activation, promotes nitric oxide production, and inhibits the activation of platelets and the coagulation cascade. Functional characterization of HDL is, therefore, necessary for precise assessment of the cardiovascular risk and effectiveness of risk reduction.

[Effects of Aging and Sex Differences on the Median Nerve: Relationship Between Nerve Conduction Study and Ultrasonographic Cross-Sectional Nerve Area].

OBJECTIVE: The aim of this study was to evaluate the relationship between nerve conduction and sonographic measurements of the median nerve, and to investigate the effects of aging and sex on nerve structure. METHODS: Measurements from both hands of 82 healthy volunteers were included in this study (45 men and 37 women, 38.9 ?17.7 years). The cross-sectional area(CSA) of the median nerve was evaluated at the carpal tunnel inlet (MA) and at the midpoint of the forearm (MB). RESULTS: The CSA of the median nerve at the MA was significantly correlated with age (r=0.501, P< 0.001), and distal motor latency (r=0.269, P<0.001). Although this study demonstrated the effects of the sex dif- ferences and aging on the CSA of the median nerve at MA, there was no significant effect at the MB. CONCLUSIONS: Our study suggests that aging could affect median nerve structure, especially at the anatomical entrapment point. [Original].

Kynurenine production mediated by indoleamine 2,3-dioxygenase aggravates liver injury in HBV-specific CTL-induced fulminant hepatitis.

UNLABELLED: Indoleamine 2,3-dioxygenase (IDO), an enzyme that is ubiquitously distributed in mammalian tissues and cells, converts tryptophan to kynurenine, and is also known as a key molecule that promotes apoptosis in lymphocytes and neurons. In this study, we established hepatitis B virus (HBV)-transgenic (Tg)/IDO-knockout (KO) mice and examined the influence of IDO in a murine fulminant hepatitis model induced by HBV-specific cytotoxic T lymphocytes (CTL). An increase of IDO expression in the livers of HBV-Tg/IDO-wild-type (WT) mice administered HBV-specific CTL was confirmed by real-time polymerase chain reaction, western blotting, and evaluating IDO activity. Plasma alanine aminotransferase (ALT) levels in HBV-Tg/IDO-KO mice after HBV-specific CTL injection significantly decreased compared with those in HBV-Tg/IDO-WT mice. An inhibitor of IDO, 1-methyl-d-tryptophan (1-MT), could also attenuated the observed liver injury induced by this HBV-specific CTL. The expression levels of cytokine and chemokine mRNAs in the livers of HBV-Tg/IDO-WT mice were higher than those in the livers of HBV-Tg/IDO-KO mice. The administration of kynurenine aggravated the liver injury in HBV-Tg/IDO-KO mice injected with HBV-specific CTL. Simultaneous injection of recombinant murine interferon (IFN-γ) and kynurenine also increased the ALT levels in HBV-Tg/IDO-KO mice. The liver injury induced by IFN-γ and kynurenine was improved in HBV-Tg/tumor necrosis factor-α-KO mice. CONCLUSION: Kynurenine and IFN-γ induced by the administration with HBV-specific CTL are cooperatively involved in the progression of liver injury in acute hepatitis model. Our results may lead to a new therapy for the acute liver injury caused by HBV infection.

Inhibition of indoleamine 2,3-dioxygenase activity enhances the anti-tumour effects of a Toll-like receptor 7 agonist in an established cancer model.

Toll-like receptor (TLR) agonists have been shown to have anti-tumour activity in basic research and clinical studies. However, TLR agonist monotherapy does not sufficiently eliminate tumours. Activation of the innate immune response by TLR agonists is effective at driving adaptive immunity via interleukin-12 (IL-12) or IL-1, but is counteracted by the simultaneous induction of immunosuppressive cytokines and other molecules, including IL-10, transforming growth factor-ß, and indoleamine 2,3-dioxygenase (IDO). In the present study, we evaluated the anti-cancer effect of the TLR7 agonist, imiquimod (IMQ), in the absence of IDO activity. The administration of IMQ in IDO knockout (KO) mice inoculated with tumour cells significantly suppressed tumour progression compared with that in wild-type (WT) mice, and improved the survival rate. Moreover, injection with IMQ enhanced the tumour antigen-specific T helper type 1 response in IDO-KO mice with tumours. Combination therapy with IMQ and an IDO inhibitor also significantly inhibited tumour growth. Our results indicated that the enhancement of IDO expression with TLR agonists in cancer treatment might impair host anti-tumour immunity while the inhibition of IDO could enhance the therapeutic efficacy of TLR agonists via the increase of T helper type 1 immune response.

Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice.

Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades the essential amino acid l-tryptophan along the kynurenine pathway, exerts immunomodulatory effects in a number of diseases. IDO expression is increased in tumor tissue and in draining lymph nodes; this increase is thought to play a role in tumor evasion by suppressing the immune response. A competitive inhibitor of IDO is currently being tested in clinical trials for the treatment of relapsed or refractory solid tumors, but the efficacy of IDO inhibition in colorectal tumors remains to be fully elucidated. In this study, we investigated the effect of IDO deficiency on colon tumorigenesis in mice by genetic deletion and pharmacological inhibition. Ido1-deficient((-/-)) mice were crossed with Apc(Min/+) mice or were administered azoxymethane with or without dextran sodium sulfate. Ido1 deficiency did not lead to significant differences in the size and number of colon tumors. Similarly, the pharmacological inhibition of IDO using 1-methyltryptophan (1-mT) also resulted in no significant differences in tumor size and number in Apc(Min/+) mice. However, Ido1 deficiency altered the immune response in the tumor microenvironment, showing a significant increase in mRNA expression of pro-inflammatory cytokines and a significant decrease in the number of Foxp3-positive regulatory T cells in the colon tumors of Ido1((-/-)) mice. Importantly, 1-mT treatment also significantly altered cytokine expression in the colon tumor tissues. These results suggest that IDO inhibition alone cannot sufficiently suppress colon cancer development in mice despite its immunomodulatory activity in the tumor microenvironment.

Inhibition of induced nitric oxide synthase enhances the anti-tumor effects on cancer immunotherapy using TLR7 agonist in mice.

Toll-like receptor (TLR) agonists have been shown to have anti-tumor activity in basic research and clinical studies. However, TLR agonist monotherapy in cancer treatment dose not sufficiently eliminate tumors. Activation of the innate immune response by TLR agonists and other pathogen-associated molecular patterns is effective for driving adaptive immunity via interleukin (IL)-12 or IL-1, but is counteracted by the simultaneous induction of immunosuppressive cytokines and other molecules, including IL-10, tumor growth factor-ß, and induced nitric oxide synthase (iNOS). In the present study, we evaluated the anticancer effect of the TLR7 agonist, imiquimod (IMQ), in the absence of iNOS. The administration of IMQ in iNOS-knockout (KO) mice implanted with tumor cells significantly suppressed tumor progression as compared to that in wild-type mice and improved the survival rate. Moreover, injection with IMQ enhanced the tumor antigen-specific Th1 response in iNOS-KO mice with tumors. The enhancement of the antigen-specific Th1 response was associated with an increase in IL-2 and IL-12b expressions in the tumor-draining lymph nodes. Combination therapy with IMQ and an iNOS inhibitor also significantly inhibited tumor growth in the established tumor model. Finally, our results indicated that the enhancement of iNOS expression through the administration with TLR agonists impairs host anti-tumor immunity, while the inhibition of iNOS could enhance the therapeutic efficacy of TLR agonists via the increase in Th1 immune response.

Pre-stimulated Mice with Carbon Tetrachloride Accelerate Early Liver Regeneration After Partial Hepatectomy.

BACKGROUND AND AIM: The liver has a high capacity of its regeneration. Most hepatic cells are quiescent unless otherwise stimulated such as their injury or ablation. A previous study suggest that pre-activated hepatic cells have a positive effect on their regeneration. In this study, we examined whether the pre-activated hepatic cells for regeneration accelerate the subsequent liver regeneration. METHODS: We administered a single injection of carbon tetrachloride (CCl4) to mice 7 days before partial hepatectomy (PHx). Liver weight/body weight ratio and several parameters for cell proliferation such as mitotic index and the number of Ki67 positive cells in the liver were examined after PHx as indexes of liver regeneration. RESULTS: Compared to control mice, those pre-stimulated with CCl4 showed earlier liver regeneration 48 h after PHx. Regardless of their accelerated regeneration, pre-stimulated mice showed less cell proliferation than did control mice during liver regeneration. Hepatic fibrosis was not observed in both control and CCl4-pretreated mice after PHx. Mice pre-treated with CCl4 showed the higher matrix metalloproteinase 9 (MMP9) expression than those pre-treated with olive oil. When matrix metalloproteinase 9 (MMP9) activity was inhibited, the pre-stimulated mice did not demonstrate accelerated liver regeneration and they returned to the original state for cell proliferations after PHx. CONCLUSIONS: Pre-activated liver by CCl4 promoted its subsequent regeneration after PHx. This was not a cause of fibrosis and partly dependent on MMP9 pre-activity rather than cell proliferation in liver. Our findings would not only provide a novel strategy for liver regeneration without cell proliferation as much as possible and also propose a new method for liver transplantation.

Atazanavir-induced urine crystals demonstrated by infrared spectroscopic analysis.

Atazanavir sulfate, an azapeptide inhibitor of HIV protease, has been associated with urolithiasis. A 60-year-old man with atazanavir-induced urinary sediment crystals verified by infrared spectroscopic analysis is described. He had been receiving highly active antiretroviral therapy (HAART) for HIV infection and also had a history of urinary lithiasis and been undergoing urinalysis once every month. Needle-shaped crystals were seen in his urine sediment and infrared spectroscopic analysis revealed that these were atazanavir crystals. Because the presence of the crystals in urine do not always reveal an abnormality in the urinary test strip analysis, the urinary sediment needed to be observed microscopically in order to prevent future urolithiasis and renal failure in this HIV patient receiving atazanavir.

[Change in Serum Levels of New Hepatic Fibrosis Marker "Mac-2 Binding Protein Glycosylation isomer (M2BPGi)" in Patients with Chronic Hepatitis C during the Treatment of Pegylated Interferon and Ribavirin].

The sustained virological response (SVR) rate in the patients with HCV has currently reached to 90% by the progression of anti-viral therapy. However, several reports demonstrated that hepatocellular carcinoma develops even in the patients with SVR. It is widely accepted that liver fibrosis plays a pivotal role in hepatocellular carcinogenesis. Thus, an accurate staging for liver fibrosis is necessary to improve long-term prognosis of hepatitis C patients. Recently, Mac-2 binding protein glycosylation isomer (M2BPGi) was identified as a novel hepatic fibrosis marker. In the present study, we compared the value of M2BPGi in serum before and after the anti-viral therapy in hepatitis C patients. The value of M2BPGi in patients with F2, F3, or F4 stagings was significantly higher than that in F1 staging. Moreover, the value of M2BPGi significantly decreased after the treatment with pegylated interferon plus ribavirin similarly to other liver fibrosis-related markers. In addition, the value of M2BPGi in patients with SVR was significantly decreased after the anti-viral therapy (P < 0.0001). The reduction of M2BPGi in SVR patients was thought to reflect the improvement of liver fibrosis, in conjunction with the reduction of viral load, after the treatment. In conclusion, the measurement of M2BPGi in serum might be useful in monitoring the improvement of liver fibrosis by anti-viral therapy.

Blockade of indoleamine 2,3-dioxygenase reduces mortality from peritonitis and sepsis in mice by regulating functions of CD11b+ peritoneal cells.

Indoleamine 2,3-dioxygenase-1 (Ido), which catalyzes the first and limiting step of tryptophan catabolism, has been implicated in immune tolerance. However, the roles of Ido in systemic bacterial infection are complicated and remain controversial. To explore this issue, we examined the roles of Ido in bacterial peritonitis and sepsis after cecal ligation and puncture (CLP) in mice by using the Ido inhibitor 1-methyl-d,l-tryptophan (1-MT), by comparing Ido(+/+) and Ido(-/-) mice, or by using chimeric mice in which Ido in the bone marrow-derived cells was deficient. Ido expression in the peritoneal CD11b(+) cells and its metabolite l-kynurenine in the serum were increased after CLP. 1-MT treatment or Ido deficiency, especially in bone marrow-derived cells, reduced mortality after CLP. Compared to Ido(+/+) mice, Ido(-/-) mice showed increased recruitment of neutrophils and mononuclear cells into the peritoneal cavity and a decreased bacterial count in the blood accompanied by increased CXCL-2 and CXCL-1 mRNA in the peritoneal cells. Ido has an inhibitory effect on LPS-induced CXCL-2 and CXCL-1 production in cultured peritoneal cells. These findings indicate that inhibition of Ido reduces mortality from peritonitis and sepsis after CLP via recruitment of neutrophils and mononuclear cells by chemokine production in peritoneal CD11b(+) cells. Thus, blockade of Ido plays a beneficial role in host protection during bacterial peritonitis and sepsis.

Induction of hepatitis B virus surface antigen-specific cytotoxic T lymphocytes can be up-regulated by the inhibition of indoleamine 2, 3-dioxygenase activity.

Cytotoxic T lymphocytes (CTLs) are thought to be major effectors involved in viral clearance during acute infections, including hepatitis B virus (HBV) infection. A persistent HBV infection is characterized by a lack of or a weak CTL response to HBV, which may be reflective of tolerance to HBV. Efficient induction of HBV-specific CTLs leads to the clearance of HBV in patients with a chronic HBV infection. Previously, we reported that α-galactosylceramide (α-GalCer), a specific natural killer T (NKT) cell agonist, enhanced the induction of HBV surface antigen (HBsAg)-specific CTLs. In the present study, we found that inhibition of indoleamine 2,3-dioxygenase (IDO) activity enhanced the induction of HBsAg-specific CTLs after immunization with HBsAg and α-GalCer. The administration of HBsAg and α-GalCer increased the production of interleukin-2 and interleukin-12b, which are crucial for the induction of HBsAg-specific CTLs. The production of these cytokines was more strongly enhanced in IDO knockout mice compared with wild-type mice. In addition, α-GalCer induced the production of IDO in CD11b(+) cells, and these cells inhibited proliferation of HBsAg-specific CTLs. Our results lead to strategies for improving the induction of HBsAg-specific CTLs.