Abstract Toll-like receptors (TLRs) are signaling receptors in the innate immune system that is a specific immunologic response to systemic bacterial infection. We investigated whether cerebral ...ischemia induced by the middle cerebral artery occlusion (MCAO) for 2 h differed in mice that lack a functional TLR3, TLR4, or TLR9 signaling pathway. TLR4, but not TLR3 or TLR9, knock-out (KO) mice had significantly smaller infarct area and volume at 24 h after ischemia-reperfusion (I/R) compared with wild-type mice. In addition, TLR4 KO mice improved in neurological deficits after I/R compared with wild-type mice. Moreover, we investigated the expression of TLR4 in the ischemic brain with immunohistochemistry. The number of TLR4-positive cells gradually increased from 1 h after MCAO to 22 h after I/R. We also examined the localization of TLR4 in the ischemic area. TLR4 was localized with CD11b-positive microglial cells in the ischemic striatum and the number of CD11b-positive microglial cells was smaller in TLR4 KO mice than in wild-type mice. In addition, we investigated the translocation of NF-κB among TLR3, 4, and 9 KO mice after I/R injury using western blotting. NF-κB's p65 subunit was decreased in TLR4 KO mice compared to wild-type mice, but not TLR3 or 9 KO mice. These data suggest that TLR4 knockout, but not TLR3 or TLR9 knockout, may play a neuroprotective role in ischemic brain injury induced by MCAO in mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Accumulating evidence indicates that cyclooxygenase (COX)-2-derived prostaglandin (PG) E(2) is involved in the development of various tumors, including colorectal cancer. However, the precise ...contribution of microsomal PGE synthase (mPGES)-1, a terminal enzyme that acts downstream of COX-2 in the PGE(2)-biosynthetic pathway, to multiple processes of tumor development is not yet fully understood. Here, we show the pro-tumorigenic role of mPGES-1 in chemical carcinogen-induced colon carcinogenesis and intrasplenic tumor transplantation models. Genetic deletion of mPGES-1 significantly reduced both the total number and size of colorectal polyps at 18 weeks after azoxymethane administration with reduced nuclear translocation of β-catenin, altered expression profiles of chemokines/cytokines and increased production of antitumorigenic PGs, prostaglandin D(2) and prostacyclin in tumor tissues. At an early stage (6 weeks), mPGES-1 deficiency significantly reduced the number of aberrant crypt foci, while its transgenic overexpression increased the number. Furthermore, the growth of intrasplenically transplanted tumor cells was suppressed in mPGES-1 knockout (KO) mice. Co-culture of tumor cells with bone marrow-derived macrophages (BM-MΦs) isolated from wild-type (WT) mice resulted in the induction of mPGES-1 in BM-MΦs and increased the growth of tumor cells in vitro, whereas mPGES-1-null BM-MΦs failed to facilitate tumor growth. The adoptive transfer of WT BM-MΦs into mPGES-1 KO mice restored the growth of transplanted tumor cells, indicating that mPGES-1 in MΦs is important for the growth of adjacent tumor cells. Taken together, our findings suggest that the inhibition of mPGES-1 is an alternative therapeutic target for colorectal and possibly other cancers.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In adults undergoing living donor liver transplantation (LDLT), the transplanted livers are partial grafts, and the portal venous pressure is higher than that observed with whole liver grafts. In ...patients undergoing LDLT concomitant with splenomegaly, portal venous flow is often diverted to collateral vessels, leading to a high risk of portal vein thrombosis. In such cases, occlusion of the collateral veins is important; however, complete occlusion of all collaterals without blocking the blood flow through the splenic artery causes portal hypertension and liver failure. We aimed to examine the effect of performing a splenectomy concomitant with LDLT to reduce portal vein complications.
Between 1991 and 2017, we performed 170 LDLT operations, including 83 in adults. For this cohort study, adult cases were divided into 2 groups. Group I was those who underwent LDLT without splenectomy (n = 60); Group II was those who underwent LDLT with splenectomy for the reduction of portal hypertension (n = 23). We investigated the incident rates of complications, including blood loss, lethal portal vein thrombosis (intrahepatic thrombosis), acute rejection, and so on. We also investigated the survival rates in both groups.
The incident rate of lethal portal vein thrombosis in Group II was significantly lower than that observed in Group I (4.4% vs 21.7%, respectively, P = .0363). There were no statistically significant differences observed between the groups with respect to blood loss, survival rates, and other such parameters.
LDLT concomitant with splenectomy might effectively reduce the occurrence of portal vein complications in adults.
•In the case of LDLT with splenomegaly, portal vein flow is often diverted to the co-lateral shunt vein and portal vein thrombosis occurs.•If the all co-lateral vein is perfectly occluded without stopping the splenic arteries, portal hypertension and liver failure often occur.•The incident rate of lethal portal vein thrombosis occurring during an LDLT with a splenectomy was significantly lower than that during LDLT without a splenectomy.•Performing an LDLT with a splenectomy may be an effective means of reducing portal complications.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Structured
Objectives
To investigate the effects of IL‐17 on IL‐6, IL‐1β, and matrix metalloproteinase (MMP‐1) production, and to compare the MMP‐1 production between the individual and combined ...effects of IL‐1β and IL‐6 in human periodontal ligament fibroblasts (HPDLF).
Materials and Methods
Human periodontal ligament fibroblasts were cultured with IL‐17 for 0.5, 1, 4, 24, 48, and 72 h, and were cultured with IL‐1β, IL‐6/sIL‐6R, or a combination of IL‐1β and IL‐6/sIL‐6R for 24 h. To measure the mRNA levels of IL‐6, IL‐1β, and MMP‐1, total RNA was extracted from the cultured HPDLF, and a real‐time PCR analysis was performed. The protein levels of IL‐6, IL‐1β, and MMP‐1 in supernatants were measured using enzyme‐linked immunosorbent assays (ELISAs).
Results
IL‐17 significantly increased the expression of IL‐6 and MMP‐1 mRNA and protein, while IL‐17 transiently increased the expression of IL‐1β mRNA. The combination of IL‐1β and IL‐6/sIL‐6R induced significantly higher levels of MMP‐1 protein than IL‐1β alone.
Conclusions
IL‐17 upregulated the production of IL‐6 and MMP‐1 sequentially in HPDLF. IL‐6/sIL‐6R may enhance the effects of IL‐1β on MMP‐1 production. The present results suggest that IL‐17 induces MMP‐1 production not only directly, but also indirectly by promoting IL‐6 production, thus resulting in the degradation of collagens in the PDL.
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CMK, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and purpose: Although microsomal prostaglandin E synthase (mPGES)‐1 is known to contribute to stroke injury, the underlying mechanisms remain poorly understood. This study examines the ...hypothesis that EP3 receptors contribute to stroke injury as downstream effectors of mPGES‐1 neurotoxicity through Rho kinase activation.
Experimental approach: We used a glutamate‐induced excitotoxicity model in cultured rat and mouse hippocampal slices and a mouse middle cerebral artery occlusion–reperfusion model. Effects of an EP3 receptor antagonist on neuronal damage in mPGES‐1 knockout (KO) mice was compared with that in wild‐type (WT) mice.
Key results: In cultures of rat hippocampal slices, the mRNAs of EP1–4 receptors were constitutively expressed and only the EP3 receptor antagonist ONO‐AE3‐240 attenuated and only the EP3 receptor agonist ONO‐AE‐248 augmented glutamate‐induced excitotoxicity in CA1 neurons. Hippocampal slices from mPGES‐1 KO mice showed less excitotoxicity than those from WT mice and the EP3 receptor antagonist did not attenuate the excitotoxicity. In transient focal ischaemia models, injection (i.p.) of an EP3 antagonist reduced infarction, oedema and neurological dysfunction in WT mice, but not in mPGES‐1 KO mice, which showed less injury than WT mice. EP3 receptor agonist‐induced augmentation of excitotoxicity in vitro was ameliorated by the Rho kinase inhibitor Y‐27632 and Pertussis toxin. The Rho kinase inhibitor HA‐1077 also ameliorated stroke injury in vivo.
Conclusion and implications: Activity of mPGES‐1 exacerbated stroke injury through EP3 receptors and activation of Rho kinase and/or Gi. Thus, mPGES‐1 and EP3 receptors may be valuable therapeutic targets for treatment of human stroke.
This article is commented on by Andreasson, pp. 844–846 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00715.x
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Toll-like receptor 5 (TLR5) has been widely studied in an inflammatory context, but the effect of TLR5 on the adaptive response to bacterial flagellin has received considerably less attention. Here, ...we demonstrate that TLR5 expression by dendritic cells (DCs) allows a 1,000-fold enhancement of T-cell sensitivity to flagellin, and this enhancement did not require the expression of NLRC4 or Myd88. The effect of TLR5 on CD4 T-cell sensitivity was independent of the adjuvant effect of flagellin and TLR5 ligation did not alter the sensitivity of ovalbumin (OVA)-specific T cells to OVA. In the spleen, the exquisite T-cell sensitivity to flagellin was regulated by CD4-CD8α- DCs and was blocked by a monoclonal antibody to TLR5. In the mesenteric lymph nodes, flagellin-specific T-cell activation was regulated by a population of CD103-CD11b+ DCs. Thus, TLR5 expression by mucosal and systemic DC subsets controls the sensitivity of the adaptive immune response to flagellated pathogens.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Liver transplantation from donors after cardiac death (DCD) provides a solution to the donor shortage. However, DCD liver grafts are associated with a high incidence of primary graft nonfunction. We ...investigated the effectiveness of subnormothermic porcine liver perfusion, before transplantation from DCD, on graft viability.
Landrace pigs (25–30 kg) were randomly allocated to 3 groups (5 per group): heart-beating (HB) graft, transplanted after a 4-hour period of cold storage (CS); DCD graft, retrieved 20 minutes after apnea-induced cardiac arrest (respiratory withdrawal) and transplanted after a 4-hour period of CS; and subnormothermic ex vivo liver perfusion (SELP) graft, retrieved in the same manner as the DCD graft but perfused with a subnormothermic oxygenated Krebs-Henseleit buffer (21–25°C, 10–15 cm H2O) for 30 minutes in a simplified dripping manner, without a machine perfusion system, after the 4-hour period of CS, and subsequently transplanted.
Although all animals in the HB group survived for >7 days, all animals in the DCD group died within 12 hours after transplantation. In the SELP group, 2 recipients survived for >7 days and another 2 recipients were killed on day 5. The survival rate was significantly better for SELP than for DCD grafts (P = .0016). The values of tumor necrosis factor α were not significantly different between the SELP and HB groups. Preserved structure of the parenchyma was observed in the SELP group on histologic examination.
A simplified subnormothermic perfusion before liver transplantation is expected to improve graft viability and survival.
•Simplified subnormothermic perfusion improves graft viability and survival.•SELP improves the survival rate of grafts compared with DCD.•The proposed simplified dripping perfusion method improves DCD liver transplant survival rate.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Toll-like receptors (TLRs) recognize malaria parasites or their metabolites; however, their physiological roles in malaria infection in vivo are not fully understood. Here, we show that myeloid ...differentiation primary response gene 88 (MyD88)-dependent TLR signaling mediates brain pathogenesis of severe malaria infection, namely cerebral malaria (CM). A significant number of MyD88-, but not TIR domain containing adaptor-inducing IFN-beta (TRIF)-deficient or wild-type (WT) mice survived CM caused by Plasmodium berghei ANKA (PbA) infection. Although systemic parasitemia was comparable, sequestration of parasite and hemozoin load in the brain blood vessels was significantly lower in MyD88-deficient mice compared with those in TRIF-deficient or WT mice. Moreover, brain-specific pathological changes were associated with MyD88-dependent infiltration of CD8+, CCR5+ T cells and CD11c+ dendritic cells, including CD11c+, NK1.1+ and B220+ cells, and up-regulation of genes such as Granzyme B, Lipocalin 2, Ccl3 and Ccr5. Further studies using mice lacking various TLRs suggest that TLR2 and TLR9, but not TLR4, 5 and 7, were involved in CM. These results strongly suggest that TLR2- and/or TLR9-mediated, MyD88-dependent brain pathogenesis may play a critical role in CM, the lethal complication during PbA infection.
In many experimental models, heart, pancreas and kidney allografts are accepted long‐term following costimulation‐targeting therapies, whereas skin, lung and intestine resist the induction of ...tolerance under the same regimens. We noted that a common feature of the resistant organs is their constant exposure to commensal microbes and hypothesized that these microorganisms may stimulate Toll‐like receptors (TLRs), promote alloresponses and prevent tolerance induction. This hypothesis prompts the predictions that TLR engagement at the time of transplantation should avert tolerance to heart allografts in animals treated with costimulation‐targeting therapies, whereas inhibition of TLR signaling should promote tolerance to skin allografts under the same conditions. Indeed, engagement of a single TLR was sufficient to prevent anti‐CD154‐mediated long‐term cardiac allograft acceptance and correlated with abolished intragraft recruitment of CD4+/FoxP3+ regulatory T cells and the development of linked‐suppression. Conversely, a lack of donor and recipient MyD88‐dependent signaling led to successful skin allograft acceptance in anti‐CD154‐treated animals. Thus, the status of TLR signaling contributes to the resistance versus susceptibility of organs to transplantation tolerance.
In a murine heart transplant model, engagement of toll‐like receptors prevents anti‐CD154‐mediated long‐term allograft acceptance and prevents intragraft recruitment of CD4+/FoxP3+ T cells.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background and purpose: Although both microsomal prostaglandin E synthase (mPGES)‐1 and cyclooxygenase (COX)‐2 are critical factors in stroke injury, but the interactions between these enzymes in ...the ischaemic brain is still obscure. This study examines the hypothesis that mPGES‐1 activity is required for COX‐2 to cause neuronal damage in ischaemic injury.
Experimental approach: We used a glutamate‐induced excitotoxicity model in cultures of rat or mouse hippocampal slices and a mouse middle cerebral artery occlusion‐reperfusion model in vivo. The effect of a COX‐2 inhibitor on neuronal damage in mPGES‐1 knockout (KO) mice was compared with that in wild‐type (WT) mice.
Key results: In rat hippocampal slices, glutamate‐induced excitotoxicity, as well as prostaglandin (PG) E2 production and PGES activation, was significantly attenuated by either MK‐886 or NS‐398, inhibitors of mPGES‐1 and COX‐2 respectively; however, co‐application of these inhibitors had neither an additive nor a synergistic effect. The protective effect of NS‐398 on the excitotoxicity observed in WT slices was completely abolished in mPGES‐1 KO slices, which showed less excitotoxicity than WT slices. In the transient focal ischaemia model, mPGES‐1 and COX‐2 were co‐localized in the infarct region of the cortex. Injection of NS‐398 reduced not only ischaemic PGE2 production, but also ischaemic injuries in WT mice, but not in mPGES‐1 KO mice, which showed less dysfunction than WT mice.
Conclusion and implications: Microsomal prostaglandin E synthase‐1 and COX‐2 are co‐induced by excess glutamate in ischaemic brain. These enzymes are co‐localized and act together to exacerbate stroke injury, by excessive PGE2 production.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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