Biomedical subjects

Hiroki Kato

Publications and source records attributed to Hiroki Kato.

At least 19 recordsLinked to original sources

PubMed2006

Cutting edge: Role of TANK-binding kinase 1 and inducible IkappaB kinase in IFN responses against viruses in innate immune cells.

TANK-binding kinase 1 (TBK1) and inducible IkappaB kinase (IKK-i) are involved in the activation of transcription factors inducing the production of type I IFNs. Although TBK1, but not IKK-i, is critical for LPS-induced IFN induction, the role of these kinases in the responses against viral infection is yet to be determined. In this study, we show that type I IFN production against various RNA viruses was completely abrogated in conventional dendritic cells (DCs) and macrophages induced from fetal liver cells lacking both TBK1 and IKK-i, whereas considerable amounts of IFN were produced in cells lacking either of them. Microarray analysis revealed that various IFN-inducible genes were also regulated by the kinases. In contrast, Fms-like tyrosine kinase 3 ligand-induced DCs produced IFN-alpha even in the absence of both TBK1 and IKK-i. Thus, these two kinases are essential and compensate each other for the regulation of IFN responses in innate immune cells except plasmacytoid DCs.

Animals↗

PubMed2006

5'-Triphosphate RNA is the ligand for RIG-I.

The structural basis for the distinction of viral RNA from abundant self RNA in the cytoplasm of virally infected cells is largely unknown. We demonstrated that the 5'-triphosphate end of RNA generated by viral polymerases is responsible for retinoic acid-inducible protein I (RIG-I)-mediated detection of RNA molecules. Detection of 5'-triphosphate RNA is abrogated by capping of the 5'-triphosphate end or by nucleoside modification of RNA, both occurring during posttranscriptional RNA processing in eukaryotes. Genomic RNA prepared from a negative-strand RNA virus and RNA prepared from virus-infected cells (but not from noninfected cells) triggered a potent interferon-alpha response in a phosphatase-sensitive manner. 5'-triphosphate RNA directly binds to RIG-I. Thus, uncapped 5'-triphosphate RNA (now termed 3pRNA) present in viruses known to be recognized by RIG-I, but absent in viruses known to be detected by MDA-5 such as the picornaviruses, serves as the molecular signature for the detection of viral infection by RIG-I.

Animals↗

PubMed2006

Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells.

Toll-like receptors (TLRs) recognize distinct microbial components and induce innate immune responses. TLR5 is triggered by bacterial flagellin. Here we generated Tlr5-/- mice and assessed TLR5 function in vivo. Unlike other TLRs, TLR5 was not expressed on conventional dendritic cells or macrophages. In contrast, TLR5 was expressed mainly on intestinal CD11c+ lamina propria cells (LPCs). CD11c+ LPCs detected pathogenic bacteria and secreted proinflammatory cytokines in a TLR5-dependent way. However, CD11c+ LPCs do not express TLR4 and did not secrete proinflammatory cytokines after exposure to a commensal bacterium. Notably, transport of pathogenic Salmonella typhimurium from the intestinal tract to mesenteric lymph nodes was impaired in Tlr5-/- mice. These data suggest that CD11c+ LPCs, via TLR5, detect and are used by pathogenic bacteria in the intestinal lumen.

Animals↗

PubMed2006

Essential role of IPS-1 in innate immune responses against RNA viruses.

IFN-beta promoter stimulator (IPS)-1 was recently identified as an adapter for retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (Mda5), which recognize distinct RNA viruses. Here we show the critical role of IPS-1 in antiviral responses in vivo. IPS-1-deficient mice showed severe defects in both RIG-I- and Mda5-mediated induction of type I interferon and inflammatory cytokines and were susceptible to RNA virus infection. RNA virus-induced interferon regulatory factor-3 and nuclear factor kappaB activation was also impaired in IPS-1-deficient cells. IPS-1, however, was not essential for the responses to either DNA virus or double-stranded B-DNA. Thus, IPS-1 is the sole adapter in both RIG-I and Mda5 signaling that mediates effective responses against a variety of RNA viruses.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Ubiquitin-proteasome-dependent degradation of mammalian ER stearoyl-CoA desaturase.

Mammalian Delta9 stearoyl-CoA desaturase 1 (SCD1) is a key enzyme in the biosynthesis of mono-unsaturated fatty acids in the endoplasmic reticulum (ER). It is a short-lived multispanning ER membrane protein, reported to be degraded by the ubiquitin-proteasome-independent pathway. We have examined SCD1 protein degradation using cultured mammalian cells. Exogenously expressed SCD1 in CHO-K1 cells was localized to the ER and turned over with a half-life of approximately 3 hours. Unexpectedly, proteasome inhibitors increased the half-life of SCD1 to approximately 6 hours. Endogenously expressed SCD1 in adipocyte-differentiated NIH 3T3-L1 cells was also rapidly degraded in a proteasome inhibitor-sensitive manner. In the presence of proteasome inhibitors, polyubiquitylated SCD1 accumulated in the ER and interacted with AAA-ATPase p97, which is involved in ER-associated degradation (ERAD). The 66-residue N-terminal segment carrying the PEST sequence is mainly responsible for SCD1 degradation and this segment induced instability in an otherwise stable ER membrane protein. Furthermore, SCD1 was degraded constitutively irrespective of the cellular levels of unsaturated fatty acids, which strictly regulate SCD1 gene expression. These findings indicate that the ubiquitin-proteasome-dependent ERAD system is also involved in constitutive SCD1 degradation.

Adenosine Triphosphatases↗

PubMed2006

Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses.

The innate immune system senses viral infection by recognizing a variety of viral components (including double-stranded (ds)RNA) and triggers antiviral responses. The cytoplasmic helicase proteins RIG-I (retinoic-acid-inducible protein I, also known as Ddx58) and MDA5 (melanoma-differentiation-associated gene 5, also known as Ifih1 or Helicard) have been implicated in viral dsRNA recognition. In vitro studies suggest that both RIG-I and MDA5 detect RNA viruses and polyinosine-polycytidylic acid (poly(I:C)), a synthetic dsRNA analogue. Although a critical role for RIG-I in the recognition of several RNA viruses has been clarified, the functional role of MDA5 and the relationship between these dsRNA detectors in vivo are yet to be determined. Here we use mice deficient in MDA5 (MDA5-/-) to show that MDA5 and RIG-I recognize different types of dsRNAs: MDA5 recognizes poly(I:C), and RIG-I detects in vitro transcribed dsRNAs. RNA viruses are also differentially recognized by RIG-I and MDA5. We find that RIG-I is essential for the production of interferons in response to RNA viruses including paramyxoviruses, influenza virus and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Furthermore, RIG-I-/- and MDA5-/- mice are highly susceptible to infection with these respective RNA viruses compared to control mice. Together, our data show that RIG-I and MDA5 distinguish different RNA viruses and are critical for host antiviral responses.

Animals↗

PubMed2006

Imaging liver metastases: review and update.

The radiologic diagnosis of liver metastasis involves detection, characterization, and tumor staging. Knowledge of the histopathologic changes that occur with metastases provides the best approach to the accurate interpretation of radiologic imaging findings, and in particular, radiologists need to choose appropriate imaging methods based on such knowledge. Because the majority of metastases are hypovascular, the merits of the routine acquisition of hepatic arterial dominant-phase images by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) are disputable. Hepatic arterial dominant-phase images may be obtained when hypervascular tumors are suspected or three-dimensional CT angiography is necessary. And, imaging during the portal venous phase is essential for detecting metastases, evaluating intrahepatic vessel invasion, and for assessing intratumoral necrosis or fibrosis. Equilibrium- to delayed-phase imaging 3-5 min after contrast administration may improve the detection of intratumoral fibrosis, and occasionally lead to more accurate tissue characterization. MRI offers diagnostic information on vascularity, amount of free water, hemorrhage, fibrosis, necrosis, and water molecule diffusion in metastases. And, liver-specific contrast agents like superparamagnetic iron oxide, liposoluble gadolinium chelate, and manganese may improve the MRI-based diagnosis of liver metastases.

Contrast Media↗

PubMed2006

Proximal aortic replacement with ascending-descending bypass for a diffuse aneurysm: report of a case.

We performed successful ascending-arch aortic replacement and concomitant ascending-to-descending aorta bypass with exclusion of a descending thoracic aneurysm, via median sternotomy, for a ruptured aortic aneurysm involving the entire thoracic aorta. The patient was an 80-year-old man with cardiopulmonary dysfunction and a history of lung tuberculosis. This operation, which has been used for complex descending thoracic aortic lesions such as recoarctation, is a feasible option for a diffuse thoracic aortic aneurysm when single-stage repair is mandatory.

Aged, 80 and over↗

PubMed2006

Pancreas: optimal scan delay for contrast-enhanced multi-detector row CT.

PURPOSE: To prospectively determine optimal scan delays for multiphasic contrast medium-enhanced imaging of the pancreas with multi-detector row computed tomography (CT). MATERIALS AND METHODS: This study was approved by an institutional review committee, and patients gave written informed consent. One hundred ninety-one patients underwent three-phase CT of the pancreas after receiving intravenous contrast medium with a fixed duration injection of 30 seconds. Patients were prospectively assigned among four groups with scan delays of 25, 45, and 65 seconds (group 1); 30, 50, and 70 seconds (group 2); 35, 55, and 75 seconds (group 3); and 40, 60, and 80 seconds (group 4). Mean CT numbers of abdominal aorta, spleen, pancreatic parenchyma, superior mesenteric artery and vein, splenic vein, and hepatic parenchyma were measured, and increases in contrast enhancement on enhanced images were assessed. Qualitative analysis was performed with a four-point scale. RESULTS: Abdominal aorta and superior mesenteric artery enhanced at a mean of 35 seconds from the start of injection (both P < .001). Pancreatic parenchyma enhanced most intensely at 35-45 seconds (P < .001) with a peak enhancement at the mean of 40 seconds. Liver parenchyma enhanced most intensely at 55-65 seconds with a peak at 60 seconds (P < .001). The mean time to peak enhancement was 45 seconds for the splenic vein and 55 seconds for the superior mesenteric vein. Qualitative results were in good agreement with quantitative results (both P < .001). CONCLUSION: With the injection protocol used in this study, optimal scan delays for imaging the pancreas were 30-35 seconds for the abdominal aorta and the superior mesenteric artery, 35-45 seconds for the pancreas, 45 seconds for the splenic vein, and 55 seconds or later for the liver.

Adult↗

PubMed2006

MDCT of the liver and hypervascular hepatocellular carcinomas: optimizing scan delays for bolus-tracking techniques of hepatic arterial and portal venous phases.

OBJECTIVE: The purpose of our study was to determine the optimal scan delays required for hepatic arterial and portal venous phase imaging and for the detection of hypervascular hepatocellular carcinomas (HCCs) in contrast-enhanced MDCT of the liver using a bolus-tracking program. SUBJECTS AND METHODS: CT images (2.5-mm collimation, 5-mm thickness with no intersectional gap) detected an increase in the CT value of 50 H in the lower thoracic aorta. The images were obtained after an IV bolus injection of 2 mL/kg of nonionic iodine contrast material (300 mg I/mL) at 4 mL/s in 171 patients, who were prospectively randomized into three groups with scans commencing at 5, 20, and 45 seconds; 10, 25, and 50 seconds; and 15, 30, and 55 seconds for the first (acquisition time: 4.3 seconds), second (4.3 seconds), and third (9.1 seconds) phases, respectively, after a bolus-tracking program. CT values of the aorta, spleen, proximal portal veins, liver parenchyma, and hepatic veins were measured. Increases in CT values from unenhanced to contrast-enhanced CT were assessed using a contrast enhancement index (CEI). Spleen-to-liver and HCC-to-liver contrasts were also assessed. A qualitative degree of contrast enhancement in each organ was prospectively assessed by two independent radiologists. RESULTS: At 10-15 seconds, the CEI of the aorta reached 300-336 H and that of the spleen reached 97-108 H without significant enhancement of liver parenchyma (15-25 H). The CEI of the proximal portal veins moderately increased (75-104 H) at 10-15 seconds, but no significant enhancement of hepatic veins was observed (24-51 H). The CEI of liver parenchyma peaked (59-63 H) at 45-55 seconds, when the CEIs of the aorta (117-125 H) and spleen (73-82 H) decreased. Spleen-to-liver contrast (81-84 H) was highest at 10-20 seconds and HCC-to-liver contrast (39-44 H) was highest at 10-15 seconds. The qualitative results correlated well with quantitative results. CONCLUSION: The optimal scan delays for hepatic arterial and portal venous phases after the bolus-tracking program detected threshold enhancement by 50 H in the lower thoracic aorta for the detection of hypervascular HCCs were 10-15 and 45-55 seconds, respectively.

Aged↗

PubMed2006

[Cell type specific involvement of RIG-I in antiviral responses].

Toll-like receptors (TLRs) play an important role in antiviral response by recognizing viral components. Recently, a RNA helicase, RIG-I, is also suggested to recognize viral double-stranded RNA. However, how these molecules contribute to viral recognition in vivo is poorly understood. Here we would like to show that RIG-I is essential for induction of type I interferons (IFNs) after infection with RNA viruses in fibroblasts and conventional dendritic cells (DCs). RIG-I induces type I IFNs by activating IRF3 via IkappaB kinase related kinases. In contrast, plasmacytoid DC, which produce large amounts of IFN-alpha, use the TLR system rather than RIG-I for viral detection. Taken together, RIG-I and the TLR system exert antiviral responses in a cell type specific manner.

Animals↗

PubMed2005

A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA.

The innate immune system recognizes nucleic acids during infection or tissue damage; however, the mechanisms of intracellular recognition of DNA have not been fully elucidated. Here we show that intracellular administration of double-stranded B-form DNA (B-DNA) triggered antiviral responses including production of type I interferons and chemokines independently of Toll-like receptors or the helicase RIG-I. B-DNA activated transcription factor IRF3 and the promoter of the gene encoding interferon-beta through a signaling pathway that required the kinases TBK1 and IKKi, whereas there was substantial activation of transcription factor NF-kappaB independent of both TBK and IKKi. IPS-1, an adaptor molecule linking RIG-I and TBK1, was involved in B-DNA-induced activation of interferon-beta and NF-kappaB. B-DNA signaling by this pathway conferred resistance to viral infection in a way dependent on both TBK1 and IKKi. These results suggest that both TBK1 and IKKi are required for innate immune activation by B-DNA, which might be important in antiviral innate immunity and other DNA-associated immune disorders.

Adaptor Proteins, Signal Transducing↗

PubMed2005

IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction.

Type I interferons are central mediators for antiviral responses. Using high-throughput functional screening of interferon inducers, we have identified here a molecule we call interferon-beta promoter stimulator 1 (IPS-1). Overexpression of IPS-1 induced type I interferon and interferon-inducible genes through activation of IRF3, IRF7 and NF-kappaB transcription factors. TBK1 and IKKi protein kinases were required for the IPS-1-mediated interferon induction. IPS-1 contained an N-terminal CARD-like structure that mediated interaction with the CARD of RIG-I and Mda5, which are cytoplasmic RNA helicases that sense viral infection. 'Knockdown' of IPS-1 by small interfering RNA blocked interferon induction by virus infection. Thus, IPS-1 is an adaptor involved in RIG-I- and Mda5-mediated antiviral immune responses.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Dendritic cells star in Vancouver.

The fast-moving field of dendritic cell (DC) biology is hard to keep pace with. Here we report on advances from the recent Keystone Symposium, "Dendritic Cells at the Center of Innate and Adaptive Immunity," organized in Vancouver, BC on Feb. 1-7, 2005 by Anne O'Garra, Jacques Banchereau, and Alan Sher. New insights into the molecular mechanisms of DC function and their influence on immune regulation, their role in infectious and autoimmune disease, and new clinical applications are highlighted.

Adaptation, Physiological↗

PubMed2005

Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction.

Toll-like receptors (TLRs) recognize microbial pathogens and trigger innate immune responses. Among TLR family members, TLR7, TLR8, and TLR9 induce interferon (IFN)-alpha in plasmacytoid dendritic cells (pDCs). This induction requires the formation of a complex consisting of the adaptor MyD88, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and IFN regulatory factor (IRF) 7. Here we show an essential role of IL-1 receptor-associated kinase (IRAK)-1 in TLR7- and TLR9-mediated IRF7 signaling pathway. IRAK-1 directly bound and phosphorylated IRF7 in vitro. The kinase activity of IRAK-1 was necessary for transcriptional activation of IRF7. TLR7- and TLR9-mediated IFN-alpha production was abolished in Irak-1-deficient mice, whereas inflammatory cytokine production was not impaired. Despite normal activation of NF-kappaB and mitogen-activated protein kinases, IRF7 was not activated by a TLR9 ligand in Irak-1-deficient pDCs. These results indicated that IRAK-1 is a specific regulator for TLR7- and TLR9-mediated IFN-alpha induction in pDCs.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Cell type-specific involvement of RIG-I in antiviral response.

Toll-like receptors (TLRs) play an important role in antiviral response by recognizing viral components. Recently, a RNA helicase, RIG-I, was also suggested to recognize viral double-stranded RNA. However, how these molecules contribute to viral recognition in vivo is poorly understood. We show by gene targeting that RIG-I is essential for induction of type I interferons (IFNs) after infection with RNA viruses in fibroblasts and conventional dendritic cells (DCs). RIG-I induces type I IFNs by activating IRF3 via IkappaB kinase-related kinases. In contrast, plasmacytoid DCs, which produce large amounts of IFN-alpha, use the TLR system rather than RIG-I for viral detection. Taken together, RIG-I and the TLR system exert antiviral responses in a cell type-specific manner.

Animals↗

PubMed2005

Solitary mediastinal lymph node metastasis of hepatocellular carcinoma: MR imaging findings.

A 65-year-old man with multiple hepatocellular carcinomas in the liver with type C viral hepatitis had a solitary mediastinal lymph node metastasis in the right paratracheal to tracheobronchial region. Surgical resection for the mediastinal metastasis was undertaken based on magnetic resonance (MR) imaging findings, suggesting its radicality. We assess the MR imaging findings and presumable pathways of lymphatic metastasis from the liver to mediastinal lymph nodes in this report.

Aged↗

PubMed2005

Use of an artificial neural network to localize accessory pathways of Wolff-Parkinson-White syndrome with 12-lead electrocardiogram.

Today, radio-frequency ablation has been shown to be a safe and effective method to treat paroxysmal tachycardia with Wolff-Parkinson-White syndrome. The many criteria reported for localizing the sites of accessory pathways from a 12-lead electrocardiogram have not proven adequate to differentiate the correct sites of accessory pathways for all situations. This study trained an artificial neural network to differentiate the varied features needed to localize 10 sites of accessory pathways. One hundred fifty patients underwent successful catheter ablation, with manifest single and antegradely conducting accessory pathways. Using the two electrocardiogram features of polarity of delta wave and R wave's share of QRS complex, an artificial neural network learned the characteristics of electrocardiogram waves for each site of the 10 accessory pathways through 90 learning cases, and an applicable network model was developed for testing. In 58 of 60 test cases (96.7%), sites of accessory pathways were localized correctly by the network. Based on the method employed in the present study, it thus becomes possible to predict the sites of accessory pathways with Wolff-Parkinson-White syndrome in more detail by using an artificial neural network with a 12-lead electrocardiogram. In the future, when this method is incorporated into a conventional automatic electrocardiogram system which could analyze delta waves and ORS complex, it will become useful to automatically diagnose the locations of the accessory pathways with Wolff-Parkinson-White syndrome in clinical practice.

Adolescent↗