EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins.

Tight junctions (TJs) connect epithelial cells and form a semipermeable barrier that only allows selective passage of ions and solutes across epithelia. Here we show that mice lacking EpCAM, a putative cell adhesion protein frequently overexpressed in human cancers, manifest intestinal barrier defects and die shortly after birth as a result of intestinal erosion. EpCAM was found to be highly expressed in the developing intestinal epithelium of wild-type mice and to localize to cell-cell junctions including TJs. Claudin-7 colocalized with EpCAM at cell-cell junctions, and the two proteins were found to associate with each other. Claudins 2, 3, 7, and 15 were down-regulated in the intestine of EpCAM mutant mice, with claudin-7 being reduced to undetectable levels. TJs in the mutant intestinal epithelium were morphologically abnormal with the network of TJ strands scattered and dispersed. Finally, the barrier function of the intestinal epithelium was impaired in the mutant animals. These results suggest that EpCAM contributes to formation of intestinal barrier by recruiting claudins to cell-cell junctions.

Efficacy and safety of sitagliptin as add-on therapy on glycemic control and blood glucose fluctuation in Japanese type 2 diabetes subjects ongoing with multiple daily insulin injections therapy.

To assess the efficacy and safety of adding sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in subjects with type 2 diabetes inadequately controlled with multiple daily insulin injections therapy (MDI). HbA1c, 1,5-anhydroglucitol (1,5-AG), body mass index (BMI), insulin doses, six-point self-measured plasma glucose (SMPG) profiles were assessed before, after 12 weeks, and after 24 weeks of MDI with 50 mg/day of sitagliptin in 40 subjects with type 2 diabetes. Safety endpoints included hypoglycemia and any adverse events. HbA1c significantly decreased during the first 12 weeks ( -0.64±0.60%), and was sustained over 24 weeks ( -0.69±0.85%). 1,5-AG increased significantly from 7.5±4.5 µg/mL at baseline to 9.6±5.5 µg/mL after 24 weeks. The bolus insulin dose at 12 weeks was decreased, and the mean plasma glucose, the SD of daily glucose, M-value, and the mean amplitude of glycemic excursions (MAGE) also decreased significantly as compared with baseline values. BMI and frequency of hypoglycemia were not changed significantly. Univariate linear regression analyses revealed that % change in HbA1c was significantly associated with BMI, and % changes in the indexes of glycemic instability (SD of daily glucose and MAGE) were significantly associated with age. In conclusion, adding sitagliptin to MDI significantly improved glycemic control and decreased the daily glucose fluctuation in subjects with type 2 diabetes inadequately controlled with MDI, without weight gain or an increase in the incidence of hypoglycemia. This trial was registered with UMIN (no. UMIN000010157).

Prevalence and characteristics of transesophageal echocardiography-related esophageal mucosal injury in patients with atrial fibrillation who underwent pulmonary vein isolation.

BACKGROUND: Transesophageal echocardiography (TEE) is the gold standard for detecting thrombi in the left atrium (LA) and left atrial appendage (LAA) prior to pulmonary vein isolation (PVI) for the treatment of atrial fibrillation (AF). Although TEE has a good safety profile, it was recently reported that TEE preceding PVI can cause esophageal mucosal injuries (EMIs). The exact mechanism remains to be elucidated. In the present study, we investigated the incidence and risk factors of TEE-related EMI (TEE-EMI) among patients who underwent PVI for AF. METHODS AND RESULTS: This study included 262 consecutive patients who underwent PVI with preoperative TEE using a 3D TEE probe and postoperative esophagogastroduodenoscopy. TEE-EMIs were observed in 16 (6.1%) patients (18 lesions), whereas PVI-related EMIs were found in 5 (1.9%) patients (8 lesions). All TEE-EMIs were observed in the upper or middle esophagus and occurred more frequently in the right region of the upper esophagus and the left anterior region of the middle esophagus; only one patient experienced mild chest discomfort. In the multivariate analysis, advanced age was an independent risk factor for TEE-EMIs (odds ratio 1.08, 95% confidence interval 1.01-1.16; P = 0.0274). CONCLUSIONS: The incidence of TEE-EMIs with 3D TEE probes was relatively high in the upper or middle esophagus, anatomically close to the LA, among patients who underwent PVI. Advanced age could pose a significant risk. These findings may warrant consideration of other methods to rule out LA/LAA thrombi, especially in elderly patients.

Pilot Study on Neonatal Screening for Methylmalonic Acidemia Caused by Defects in the Adenosylcobalamin Synthesis Pathway and Homocystinuria Caused by Defects in Homocysteine Remethylation.

Neonatal screening (NS) for methylmalonic acidemia uses propionylcarnitine (C3) as a primary index, which is insufficiently sensitive at detecting methylmalonic acidemia caused by defects in the adenosylcobalamin synthesis pathway. Moreover, homocystinuria from cystathionine ß-synthase deficiency is screened by detecting hypermethioninemia, but methionine levels decrease in homocystinuria caused by defects in homocysteine remethylation. To establish NS detection of methylmalonic acidemia and homocystinuria of these subtypes, we evaluated the utility of indices (1) C3 ≥ 3.6 µmol/L and C3/acetylcarnitine (C2) ≥ 0.23, (2) C3/methionine ≥ 0.25, and (3) methionine < 10 µmol/L, by retrospectively applying them to NS data of 59,207 newborns. We found positive results in 116 subjects for index (1), 37 for (2), and 15 for (3). Second-tier tests revealed that for index 1, methylmalonate (MMA) was elevated in two cases, and MMA and total homocysteine (tHcy) were elevated in two cases; for index 2 that MMA was elevated in one case; and for index 3 that tHcy was elevated in one case. Though data were anonymized, two cases identified by index 1 had been diagnosed with maternal vitamin B12 deficiency during NS. Methylene tetrahydrofolate reductase deficiency was confirmed for the case identified by index 3, which was examined because an elder sibling was affected by the same disease. Based on these data, a prospective NS study is underway.

The effect of appropriate eating habits, depressive state, and social support on postoperative symptom experience among Japanese postgastrectomy patients.

Postoperative symptoms have a major impact on the quality of life of postgastrectomy patients. This study examined the effect of potential risk factors other than medical perspectives (type of surgery or reconstruction technique) on postoperative symptom experience. Subjects were 82 Japanese postgastrectomy patients (mean age = 63.63 years, SD = 10.21; men = 50, women = 32). To control the surgical effect on symptom experience, subjects were limited to only those who had undergone distal subtotal gastrectomy and been discharged within the past 3 years without indication of recurrence. Main study variables were attribute, health status (disease stage, adjuvant therapy, time since surgery, postoperative symptoms and their frequency), eating habits, depression, and emotional support. The result showed that only depression (beta = .24, p < .05) was a significant predictor of postoperative symptoms. Frequency of symptoms was significantly predicted by marital status (beta = -.32) and depression (beta = .21). Health status and eating habits did not contribute to the incidence of postoperative symptoms among the subjects. The results suggest that to control the postoperative symptoms, encouraging the patient to develop healthier eating habits, enhancing psychological status, and providing appropriate social support may be needed.

Loss of Fam60a, a Sin3a subunit, results in embryonic lethality and is associated with aberrant methylation at a subset of gene promoters.

We have examined the role of Fam60a, a gene highly expressed in embryonic stem cells, in mouse development. Fam60a interacts with components of the Sin3a-Hdac transcriptional corepressor complex, and most Fam60a-/- embryos manifest hypoplasia of visceral organs and die in utero. Fam60a is recruited to the promoter regions of a subset of genes, with the expression of these genes being either up- or down-regulated in Fam60a-/- embryos. The DNA methylation level of the Fam60a target gene Adhfe1 is maintained at embryonic day (E) 7.5 but markedly reduced at E9.5 in Fam60a-/- embryos, suggesting that DNA demethylation is enhanced in the mutant. Examination of genome-wide DNA methylation identified several differentially methylated regions, which were preferentially hypomethylated, in Fam60a-/- embryos. Our data suggest that Fam60a is required for proper embryogenesis, at least in part as a result of its regulation of DNA methylation at specific gene promoters.

Absence of CC chemokine receptor 8 enhances innate immunity during septic peritonitis.

An effective clearance of microbes is crucial in host defense during infection. In the present study, we demonstrate that CC chemokine receptor 8 (CCR8) skews innate immune response during septic peritonitis induced by cecal ligation and puncture (CLP). CCR8 was expressed in resident peritoneal macrophages and elicited leukocytes during CLP in the wild-type CCR8+/+ mice. CCR8-/- mice were resistant to CLP-induced lethality relative to CCR8+/+ mice, and this resistance was associated with an augmented bacterial clearance in CCR8-/- mice. In vitro, peritoneal macrophages from CCR8-/- mice, but not neutrophils, exhibited enhanced bactericidal activities relative to those from CCR8+/+ mice. Upon stimulation with the bacterial component LPS, elevated levels of superoxide generation, lysosomal enzyme release, and nitric oxide generation, effector molecules for bacterial killing were detected in CCR8-/- macrophages relative to CCR8+/+ macrophages. In addition, CCR8-/- macrophages produced significantly higher levels than CCR8+/+ macrophages of several cytokines and chemokines known to augment bactericidal activities of leukocytes that include TNF-alpha, IL-12, macrophage-derived chemokine (MDC/CCL22), macrophage inflammatory protein (MIP)-2, and KC. Altogether, these results indicate that CCR8 may have a negative impact on host defense during septic peritonitis, providing a new paradigm for the role of CCR8 in innate immunity.

Correction of impaired calmodulin binding to RyR2 as a novel therapy for lethal arrhythmia in the pressure-overloaded heart failure.

BACKGROUND: Calmodulin (CaM) is a key modulator of the channel gating function of the ryanodine receptor (RyR). OBJECTIVE: The purpose of this study was to investigate the pathogenic role of RyR-bound CaM in diastolic Ca2+ leakage from the sarcoplasmic reticulum and arrhythmogenesis in pressure-overloaded heart failure. METHODS: Pressure overload was induced in 12-week-old mice by transverse aortic constriction (TAC) using a 27-gauge needle. RESULTS: TAC operation for 8 weeks produced a significant increase in left ventricular end-diastolic diameter and frequent occurrence of lethal arrhythmias after infusion of epinephrine and caffeine in TAC mice. The amount of RyR-bound CaM decreased significantly in TAC mice compared with sham mice. The apparent affinity of CaM binding to RyR decreased in pressure-overloaded cells compared with sham cells and untreated cells. High-affinity calmodulin (HA-CaM; ie, CaM whose binding affinity to RyR was significantly increased) restored a normal level of CaM-RyR binding properties in pressure-overloaded cells. HA-CaM corrected abnormally increased Ca2+ spark frequency in the pressure-overloaded cells to the level seen in the sham cells. The frequency of spontaneous Ca2+ transients in TAC cells during and after 1-5 Hz of field stimulation was 44%, whereas it was significantly attenuated by HA-CaM but not with CaM. CONCLUSION: Several disorders in the RyR channel function characteristic of pressure-overloaded cells (increased spontaneous Ca2+ leakage, delayed afterdepolarization, triggered activity, Ca2+ spark frequency, spontaneous Ca2+ transients) are caused by deteriorated CaM binding to RyR2. These disorders could be rectified by restoring normal CaM binding to RyR2.

Comparison of the efficacy of sitagliptin and glimepiride dose-up in Japanese patients with type 2 diabetes poorly controlled by sitagliptin and glimepiride in combination.

AIMS/INTRODUCTION: The goal of the study was to examine the effects of sitagliptin dose-up or glimepiride dose-up in Japanese patients with type 2 diabetes who were controlled inadequately by sitagliptin and glimepiride in combination. MATERIALS AND METHODS: A multicenter, prospective, randomized, open-label study was carried out in 50 patients with type 2 diabetes treated with sitagliptin and low-dose glimepiride. The patients were randomly assigned to receive the addition of 50 mg/day sitagliptin or 0.5 mg/day glimepiride. The primary end-point was the percentage change in glycated hemoglobin (HbA1c). RESULTS: During a follow-up period, the difference in the percentage changes in HbA1c between the two groups was not significant (P = 0.13). However, HbA1c was significantly decreased by glimepiride dose-up (P < 0.01 vs baseline), but not by sitagliptin dose-up (P = 0.74). Univariate linear regression analyses showed that the percentage change in HbA1c was significantly associated with the serum level of arachidonic acid (AA) in both groups. CONCLUSIONS: There was no significant difference in the HbA1c-lowering effects between the two groups. However, a significant HbA1c-lowering effect from baseline of glimepiride dose-up was found, and the AA level showed a negative correlation with the decrease in HbA1c in the sitagliptin dose-up group, but a positive correlation in the glimepiride dose-up group. These findings suggest that the AA level is associated with HbA1c reduction in response to dose-up with these drugs in patients with type 2 diabetes in a combination therapy with sitagliptin and glimepiride. This trial was registered with UMIN (no. 000009544).

Effects of olmesartan, an angiotensin II receptor blocker, on peripheral insulin sensitivity in Japanese subjects with type 2 diabetes and hypertension.

OBJECTIVE: Several studies have assessed the efficacy of angiotensin receptor blockers (ARBs) on peripheral insulin sensitivity using the euglycemic hyperinsulinemic clamp technique in hypertensive subjects. However, these subjects were mostly non-diabetic, and some studies showed that ARB treatment did not improve insulin sensitivity. Thus, it is still uncertain whether ARBs could improve insulin sensitivity in subjects with hypertension and diabetes. Therefore, we evaluated the effect of olmesartan on peripheral insulin sensitivity in subjects with type 2 diabetes and hypertension using M/I value during the euglycemic-hyperinsulinemic clamp technique. METHODS: We enrolled 10 Japanese subjects with type 2 diabetes and hypertension who had never taken antihypertensive agents. Their blood pressure, fasting plasma glucose level, HbA1c and glucose utilization rate during euglycemic-hyperinsulinemic clamp (M/I value) were examined before and after 6 months of treatment with 10-20 mg/day olmesartan (mean: 13.0 mg/day). RESULTS: Blood pressure decreased significantly from 156/88 mmHg before starting olmesartan to 135/76 mmHg after 6 months of olmesartan treatment. The mean M/I value increased significantly from 6.33 ± 3.19 (mg/kg/min/mU/L) × 100 to 8.11 ± 4.20 (mg/kg/min/mU/L) × 100. Peripheral insulin sensitivity improved in eight out of ten subjects. Fasting glucose levels and HbA1c levels also decreased significantly. CONCLUSION: These results indicate that olmesartan improves glucose metabolism by improving the peripheral insulin sensitivity in subjects with type 2 diabetes.

Ezetimibe improves glucose metabolism by ameliorating hepatic function in Japanese patients with type 2 diabetes.

UNLABELLED: Aims/Introduction: Several experimental studies have shown that ezetimibe improves steatosis and insulin resistance in the liver. This suggests that ezetimibe may improve glucose metabolism, as well as lipid metabolism, by inhibiting hepatic lipid accumulation. Therefore, we compared HbA1c levels after 3 months ezetimibe treatment with baseline levels in patients with type 2 diabetes and examined the factors associated with reductions in HbA1c following ezetimibe administration. MATERIALS AND METHODS: Lipid profiles, hepatic function, and HbA1c were assessed before and after 3 months treatment with 10 mg/day ezetimibe in 96 patients with type 2 diabetes and hypercholesterolemia. Regression analysis was used to investigate associations between metabolite levels and the percentage change in HbA1c. RESULTS: Low-density lipoprotein-cholesterol was significantly lower after 3 months treatment compared with baseline, and HbA1c decreased in approximately 50% of patients. Univariate linear regression analyses showed that changes in HbA1c were significantly associated with serum alanine aminotransferase (ALT), the aspartate aminotransferase (AST)/ALT ratio, and age. Two-tailed chi-square tests revealed that serum ALT ≥35 IU/L and an AST/ALT ratio <1.0 were significantly associated with decreases in HbA1c following ezetimibe administration. CONCLUSIONS: The results of the present study indicate that ezetimibe may improve glucose metabolism. Serum ALT levels and the AST/ALT ratio were useful predictors of a glucose metabolism response to ezetimibe. This trial was registered with UMIN (no. UMIN000005307). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00147.x, 2011).

Multiple infected aortic aneurysms repaired by staged in situ graft replacement.

The development of multiple infected aortic aneurysms is extremely rare, and treatment remains challenging. We report here a 72-year-old man with multiple infected aortic aneurysms in whom a staged in situ graft replacement for the aortic arch and pararenal abdominal aorta was successfully performed. A rifampicin-bonded graft seemed to be effective in preventing postoperative infection. Perioperative control of infection played a key role in the patient's surviving this critical condition.

Predictors of coronary heart disease in Japanese patients with type 2 diabetes: Screening for coronary artery stenosis using multidetector computed tomography.

UNLABELLED: Aims/Introduction: Multidetector computed tomography (MDCT) coronary angiography has been applied as a tool for non-invasive evaluation of the coronary arteries. The purpose of the present study was to evaluate the effectiveness of MDCT in screening for coronary artery disease (CAD), and to identify the indications for screening in diabetes patients with CAD. MATERIALS AND METHODS: The study population consisted of 52 Japanese type 2 diabetes patients who underwent examination with a 64-slice MDCT scanner, electrocardiogram (ECG), echocardiography and ultrasonographic scanning of the carotid arteries. Regression analysis was carried out to assess the correlation between MDCT results and CAD risk factors. RESULTS: Stenosis of the coronary artery was detected in 19/52 patients. Of the 19 patients, 7 patients had no symptoms, including chest pain, and no ischemic changes in ECG. Significant differences between patients with stenosis and those without stenosis were detected by mean IMT (1.21 vs 0.95 mm), and duration of diabetes (20 vs 13 years). Two-tailed χ(2)-test showed that a duration of diabetes of more than 20 years (odds ratio 6.222) and more than 1.1 mm of mean-IMT (odds ratio 4.600) significantly correlated with the stenosis. CONCLUSIONS: It was shown that MDCT is useful in detecting coronary artery stenosis in diabetic patients without symptoms of CAD or ECG abnormality, and the predictors of CAD are mean IMT and duration of diabetes. It is recommended that patients with more than 1.1 mm mean IMT at the carotid artery and/or more than 20 years duration of diabetes should be screened for CAD by carrying out MDCT.

The effect of psychological intervention on personality change, coping, and psychological distress of Japanese primary breast cancer patients.

The purpose of this study is to estimate the effectiveness of psychological intervention on personality change, enhancing perceived emotional support, and, ultimately, assisting in the adaptive coping and psychological well-being of Japanese primary breast cancer patients. The intervention consists of 3 sessions that include providing medical and psychological information and counseling using the structured association technique. The participants were 28 primary breast cancer patients (14 for the experimental group and 14 for the control group). Participants were assessed at 3 to 4 days after surgery (preintervention) and 3 months (postintervention) and 6 months (follow-up) after discharge using 5 scales: the self-repression scale, the Japanese version of the self-esteem scale, the emotional support scale, the Japanese version of the Mental Adjustment to Cancer Scale, and the Japanese version of the Hospital Anxiety and Depression Scale. The intervention seemed to have enhanced the short-term personality change, adaptive coping, and psychological well-being of primary breast cancer patients. However, further trials will be needed with larger samples to corroborate the findings.

A case of primary small cell carcinoma of the liver that was treated with chemotherapy.

Primary small cell carcinoma (SSC) of the liver is very rare in Japan and only ten cases have been reported worldwide. We report herein the case of a 77-year-old man with primary SCC of the liver. He had a tumor over 10 cm in diameter which was localized in the right lobe of the liver and had invaded the right diaphragm. In laboratory tests, high serum levels of lactate dehydrase and neuron-specific enolase were observed. A biopsy specimen showed that the tumor cells were similar in cytology to a pulmonary SCC. The patient was first treated with carboplatin and etoposide according to the therapy protocol for pulmonary SCC and then with a regimen using etoposid and cisplatinum, resulting in an unfavorable outcome. We discuss the clinical course and therapy of extra-pulmonary SCC and review the literature of the cases previously reported.

The effect of postoperative symptom experience, and personality and psychosocial factors on depression among postgastrectomy patients in Japan.

Depression, the most common affective disorder in cancer, has a major impact on quality of life. Various risk factors may interact and affect a cancer patient's depressive state. The purpose of this study was to examine the relationships between depression and postoperative symptom experience, personality, and psychosocial factors in Japanese gastrectomy patients. Causal relationships of these variables were also estimated. Eighty-two Japanese gastrectomy patients (M age = 63.63 years, SD = 10.21; men = 50, women = 32), who had been discharged within the last 3 years with no indication of cancer recurrence, participated in the study. Results showed significant correlations between depression and age, time-since-discharge, postoperative symptom experience, frequency of symptoms, self-esteem, and emotional support. Path analysis showed sufficient goodness of fit index (GFI = 0.993, AGFI = 0.963). Interpersonal dependency, emotional support, and marital status showed a direct effect on self-esteem, which, along with postoperative symptom experience, had a direct effect on depression. Findings provide a useful reference point for further understanding the mental health condition of postgastrectomy patients.

Stat3 in resident macrophages as a repressor protein of inflammatory response.

Inflammation is counterbalanced by anti-inflammatory cytokines such as IL-10, in which Stat3 mediates the signaling pathway. In this study, we demonstrate that resident macrophages, but not other cell types, are important targets of IL-10 in a murine model of acute peritonitis. Injection of thioglycollate i.p. induced a considerable number of neutrophils and macrophages in the peritoneum, which was significantly augmented in mice with a cell-type specific disruption of the Stat3 gene in macrophages and neutrophils (LysMcre/Stat3flox/- mice). The augmented leukocyte infiltration was accompanied by increased peritoneal levels of TNF-alpha, MIP-2, KC chemokine (KC), and MCP-1/CCL2. Stat3 was tyrosine phosphorylated in peritoneal resident macrophages as well as infiltrating leukocytes in the littermate controls, suggesting that Stat3 in either or both of these cells might play a regulatory role in inflammation. The peritoneal levels of TNF-alpha, MIP-2, KC, and MCP-1 were similarly elevated in LysMcre/Stat3flox/- mice rendered leukopenic by cyclophosphamide treatment as compared with the controls. Adoptive transfer of resident macrophages from LysMcre/Stat3flox/- mice into the control littermates resulted in increases in the peritoneal level of TNF-alpha, MIP-2, KC, and MCP-1 after i.p. injection of thioglycollate. Under these conditions, control littermates harboring LysMcre/Stat3flox/- macrophages exhibited an augmented leukocyte infiltration relative to those received control macrophages. Taken together, these data provide evidence that resident macrophages, but not other cell types, play a regulatory role in inflammation through a Stat3 signaling pathway. Stat3 in resident macrophages appears to function as a repressor protein in this model of acute inflammation.

Gene-environment interactions between alcohol drinking and the MTHFR C677T polymorphism impact on esophageal cancer risk: results of a case-control study in Japan.

Folate takes part in two biological pathways involved in DNA methylation and synthesis, and a potential protective influence of this nutrient chemical against carcinogenicity has been recognized in several sites, including the esophagus. Therefore, the functional polymorphisms in genes encoding folate metabolizing enzymes, MTHFR C677T and MTR A2756G, might be suspected of impacting on esophageal cancer risk. We therefore conducted a matched case-control study of 165 esophageal cancer cases and 495 non-cancer controls to clarify associations among folate intake, MTHFR C677T and MTR A2756G polymorphisms, and esophageal cancer risk. Gene-environment interactions between the two polymorphisms, and drinking and smoking were also evaluated. Folate consumption and MTHFR 677TT were associated with a non-significant tendency for decreased risk while the MTR genotypes did not show any links in themselves; further, when analysis was limited to heavy drinkers, the MTHFR TT genotype significantly decreased esophageal cancer risk [odds ratio (OR) = 0.27, 95% confidence interval (CI), 0.09-0.76]. The OR for the gene-environment interaction between heavy drinking and the 677TT genotype in the case-only design was 0.31 (95% CI, 0.10-0.94), indicating risk with heavy drinking to be 69% decreased in individuals harboring the 677TT genotype. We failed to find any significant interaction between either of the polymorphisms and smoking.

Aberrant inflammation and lethality to septic peritonitis in mice lacking STAT3 in macrophages and neutrophils.

Stat3 is a transcription factor mediating anti-inflammatory properties of IL-10. In the present study, we demonstrate a pivotal role of Stat3 expressed in innate immune cells during septic peritonitis induced by cecal ligation and puncture (CLP). Mice with targeted disruption of Stat3 in macrophages and neutrophils were succumbed to septic peritonitis induced by CLP. The mice displayed an excessive local and systemic inflammation relative to the control mice, an event that was accompanied by substantial increases in the level of multiple cytokines. Hepatic and renal injury was significantly exacerbated in mice with Stat3 deficiency. Despite enhanced inflammatory responses, the mice failed to facilitate bacterial clearance as compared with the control mice. In addition, the mice exhibited an increased lethality after i.p. inoculation of live bacteria recovered from CLP-mice. In vitro, resident peritoneal macrophages from mice with Stat3 deficiency impaired bactericidal activity relative to the control whereas productions of inflammatory cytokines were significantly augmented when cells were stimulated with a synthetic lipopeptide, macrophage-activating lipopeptide-2 and LPS. Elicited macrophages and neutrophils with Stat3 deficiency also impaired bactericidal activity as compared with those with Stat3. Lysosomal enzyme release, an effector molecule for bacterial clearance, was significantly decreased in elicited leukocytes with Stat3 deficiency while increasing the production of inflammatory cytokines. Altogether, these results suggest that macrophage/neutrophil-specific STAT3 is crucial in not only modulating multiple organ failure associated with systemic inflammation but also intensifying the bactericidal activity, which highlight the significance of cell-specific Stat3 in the protective immunity during sepsis.