Details of a Researcher - YOKOTA Shinichi

Papers - YOKOTA Shinichi

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Serum heat shock protein 47 levels are elevated in acute exacerbation of idiopathic pulmonary fibrosis

Tomoyuki Kakugawa, Shin-ichi Yokota, Yuji Ishimatsu, Tomayoshi Hayashi, Shota Nakashima, Shintaro Hara, Noriho Sakamoto, Hiroshi Kubota, Mariko Mine, Yasuhiro Matsuoka, Hiroshi Mukae, Kazuhiro Nagata, Shigeru Kohno

CELL STRESS & CHAPERONES ( SPRINGER ) 18 ( 5 ) 581 - 590 2013.09 [Refereed]

Little is known about the pathophysiology of acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF). Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is essential for biosynthesis and secretion of collagen molecules. Previous studies in experimental animal fibrosis models have shown that downregulation of HSP47 expression reduces collagen production and diminishes fibrosis progression. In this study, serum HSP47 levels were evaluated to elucidate pathogenic differences involving HSP47 between AE-IPF and stable (S)-IPF. Subjects comprised 20 AE-IPF and 33 S-IPF patients. Serum levels of HSP47, Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-A, SP-D, and lactate dehydrogenase (LDH) were measured. Immunohistochemical analysis of lung HSP47 expression was determined in biopsy and autopsy tissues diagnosed as diffuse alveolar damage (DAD) and usual interstitial pneumonia (UIP). Serum levels of HSP47 were significantly higher in AE-IPF than in S-IPF patients, whereas serum levels of KL-6, SP-A, and SP-D did not differ significantly. Receiver operating characteristic curves revealed that HSP47 was superior for discriminating AE-IPF and S-IPF. The cutoff for HSP47 resulting in the highest diagnostic accuracy was 559.4 pg/mL; sensitivity, specificity, and diagnostic accuracy were 100.0 %, 93.9 %, and 96.2 %, respectively. Immunohistochemical analysis revealed that pulmonary HSP47 expression was greater in DAD than UIP tissues. Serum HSP47 was significantly higher in AE-IPF than in S-IPF patients, suggesting that underlying fibrogenic mechanisms involving HSP47 differ in the two conditions.

Characterization of a Lactobacillus gasseri JCM 1131(T) Lipoteichoic Acid with a Novel Glycolipid Anchor Structure

Tsukasa Shiraishi, Shin-ichi Yokota, Naoki Morita, Satoru Fukiya, Satoru Tomita, Naoto Tanaka, Sanae Okada, Atsushi Yokota

APPLIED AND ENVIRONMENTAL MICROBIOLOGY ( AMER SOC MICROBIOLOGY ) 79 ( 10 ) 3315 - 3318 2013.05 [Refereed]

Positive Relationship Between a Polymorphism in Helicobacter pylori Neutrophil-Activating Protein A Gene and Iron-Deficiency Anemia

Shin-ichi Yokota, Nariaki Toita, Soh Yamamoto, Nobuhiro Fujii, Mutsuko Konno

HELICOBACTER ( WILEY-BLACKWELL ) 18 ( 2 ) 112 - 116 2013.04 [Refereed]

Background Numerous studies have suggested a link between iron-deficiency anemia (IDA) and Helicobacter pylori infection. Previously, we found that strains isolated from IDA patients showed higher levels of Fe ion uptake and Fe-ion-dependent rapid proliferation than those of strains derived from patients without IDA. Materials and Methods Twenty-four H.pylori strains from IDA patients (IDA strains) and 25 strains from patients who had H.pylori gastritis without anemia (non-IDA strains) were examined. Their nucleotide sequences of napA, fur, and feoB, which contribute to Fe ion uptake, were determined. Results Numerous polymorphisms of the three genes were found in both strains. Frequency of neutrophil-activating protein A (NapA), which encoded by napA, with threonine at amino acid residue No. 70 (Thr70-type NapA) was significantly higher in IDA strains than in non-IDA strains. Strains with Thr70-type NapA showed significantly higher levels of Fe3+ and Fe2+ uptake than did strains with other types, Ser70-type of NapA, which is found in standard strains. Other significantly different occurrences of polymorphisms between IDA and non-IDA groups were not observed in these genes. Conclusion The results suggest that H.pylori strains with Thr70-type NapA have enhanced Fe ion uptake ability and are associated with the pathogenesis of IDA.

Contribution of the AcrAB-TolC efflux pump to high-level fluoroquinolone resistance in Escherichia coli isolated from dogs and humans

Toyotaka Sato, Shin-Ichi Yokota, Torahiko Okubo, Kanako Ishihara, Hiroshi Ueno, Yasukazu Muramatsu, Nobuhiro Fujii, Yutaka Tamura

Journal of Veterinary Medical Science 75 ( 4 ) 407 - 414 2013 [Refereed]

Fluoroquinolone resistance is mainly caused by mutations in quinolone resistance-determining regions of DNA gyrase and topoisomerase IV in Escherichia coli. The AcrAB-TolC efflux pump contributes to resistance against fluoroquinolone and other antimicrobials. In this study, we investigated a high-level mechanism of fluoroquinolone resistance in E. coli that was isolated from human clinical samples and canine fecal samples. E. coli strains with high levels of fluoroquinolone resistance have been found to be frequently resistant to cephalosporins. Strains with high-level fluoroquinolone resistance exhibited lower intracellular enrofloxacin (ENR) concentrations, higher expression of AcrA, and a greater reduction in the fluoroquinolone minimum inhibitory concentration for treatment with an efflux pump inhibitor. The frequency of strains with enhanced ENR resistance selection and the survival rate of E. coli in the presence of ENR in vitro were correlated well with AcrA protein expression levels in the parental strains. These results suggest that AcrAB-TolC efflux pump over-expression is related to high-level fluoroquinolone resistance and the selection of strains with enhanced fluoroquinolone resistance. © 2013 The Japanese Society of Veterinary Science.

Clonality analysis of helicobacter pylori in patients isolated from several biopsy specimens and gastric juice in a Japanese urban population by random amplified polymorphic DNA fingerprinting

Nariaki Toita, Shin-Ichi Yokota, Nobuhiro Fujii, Mutsuko Konno

Gastroenterology Research and Practice 2013 721306 2013 [Refereed]

Background. The number of Helicobacter pylori clones infecting a single host has been discussed in numerous reports. The number has been suggested to vary depending on the regions in the world. Aim. The purpose of this study was to examine the number of clones infecting a single host in a Japanese urban population. Materials and Methods. Thirty-one Japanese patients undergoing upper gastrointestinal endoscopy were enrolled in this study. H. pylori isolates (total 104 strains) were obtained from biopsy specimens (antrum, corpus, and duodenum) and gastric juice. Clonal diversity was examined by the random amplified polymorphic DNA (RAPD) fingerprinting method. Results. The RAPD fingerprinting patterns of isolates from each patient were identical or very similar. And the isolates obtained from several patients with 5- to 9-year intervals showed identical or very similar RAPD patterns. Conclusion. Each Japanese individual of an urban population is predominantly infected with a single H. pylori clone. © 2013 Nariaki Toita et al.

Fluoroquinolone resistance mechanisms in an Escherichia coli isolate, HUE1, without quinolone resistance-determining region mutations

Toyotaka Sato, Shin-Ichi Yokota, Ikuo Uchida, Torahiko Okubo, Masaru Usui, Masahiro Kusumoto, Masato Akiba, Nobuhiro Fujii, Yutaka Tamura

Frontiers in Microbiology ( Frontiers Research Foundation ) 4 ( MAY ) 125 2013 [Refereed]

Fluoroquinolone resistance can cause major clinical problems. Here, we investigated fluoroquinolone resistance mechanisms in a clinical Escherichia coli isolate, HUE1, which had no mutations quinolone resistance-determining regions (QRDRs) of DNA gyrase and topoisomerase IV. HUE1 demonstrated MICs that exceeded the breakpoints for ciprofloxacin, levofloxacin, and norfloxacin. HUE1 harbored oqxAB and qnrS1 on distinct plasmids. In addition, it exhibited lower intracellular ciprofloxacin concentrations and higher mRNA expression levels of efflux pumps and their global activators than did reference strains. The genes encoding AcrR (local AcrAB repressor) and MarR (MarA repressor) were disrupted by insertion of the transposon IS3-IS629 and a frameshift mutation, respectively. A series of mutants derived from HUE1 were obtained by plasmid curing and gene knockout using homologous recombination. Compared to the MICs of the parent strain HUE1, the fluoroquinolone MICs of these mutants indicated that qnrS1, oqxAB, acrAB, acrF, acrD, mdtK, mdfA, and tolC contributed to the reduced susceptibility to fluoroquinolone in HUE1. Therefore, fluoroquinolone resistance in HUE1 is caused by concomitant acquisition of QnrS1 and OqxAB and overexpression of AcrAB-TolC and other chromosome-encoded efflux pumps. Thus, we have demonstrated that QRDR mutations are not absolutely necessary for acquiring fluoroquinolone resistance in E. coli. © 2013 Sato, Yokota, Uchida, Okubo, Usui, Kusumoto, Akiba, Fujii and Tamura.

High Prevalence of Cross-Resistance to Aminoglycosides in Fluoroquinolone-Resistant Escherichia coli Clinical Isolates

Naoyuki Tsukamoto, Yasuo Ohkoshi, Torahiko Okubo, Toyotaka Sato, Osamu Kuwahara, Nobuhiro Fujii, Yutaka Tamura, Shin-ichi Yokot

CHEMOTHERAPY ( KARGER ) 59 ( 5 ) 379 - 384 2013 [Refereed]

Background: Multidrug-resistant Escherichia coli, especially a lineage of 025b:H4-ST131, has increased and spread worldwide. The surveillance of cross-resistance of E. coli is necessary. Methods: Cross-resistance to fluoroquinolones (FQs) and aminoglycosides (AGs) was examined in E. coli isolated in Hokkaido Prefecture, Japan, between 2008 and 2009. Results: Gentamicin (GEN) resistance was more common in FQ-resistant isolates (30/112 strains; 26.8%) than in FQ-susceptible isolates (2/100 strains; 2%). The frequency of GEN resistance was similar in two groups of FQ-resistant strains, 025b:H4-ST131 genotype (22/87 strains; 25.3%) and a group of other FQ-resistant genotypes (8/25 strains; 32.0%). The main AG resistance gene was aac(3)-II (87.5% of GEN-resistant strains). The only amikacin-resistant strain which was FQ resistant carried the aac(6')-Ib-cr gene. CTX-M type extended-spectrum beta-lactamase (ESBL) genes were also found in FQ-resistant strains at a high frequency. However, the number of strains with both ESBL and AG-modifying enzyme genes was relatively low (8 strains). Conclusion: All FQ-resistant strains, not only 025b:H4-ST131, appeared to preferentially acquire ESBL genes and/or genes encoding AG-modifying enzymes; however, the acquisitions of these genes seemed to occur independently. (C) 2014 S. Karger AG, Basel

Imiquimod Suppresses Propagation of Herpes Simplex Virus 1 by Upregulation of Cystatin A via the Adenosine Receptor A(1) Pathway

Yuji Kan, Tamaki Okabayashi, Shin-ichi Yokota, Soh Yamamoto, Nobuhiro Fujii, Toshiharu Yamashita

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY ) 86 ( 19 ) 10338 - 10346 2012.10 [Refereed]

Imiquimod is recognized as an agonist for Toll-like receptor 7 (TLR7) in immunocompetent cells. TLR7, as well as TLR3 and TLR8, triggers the immune responses, such as the production of type I interferons (IFNs) and proinflammatory cytokines via recognition of viral nucleic acids in the infected cells. In this study, we proposed that imiquimod has an IFN-independent antiviral effect in nonimmune cells. Imiquimod, but not resiquimod, suppressed replication of human herpes simplex virus 1 (HSV-1) in FL cells. We analyzed alternation of gene expression by treatment with imiquimod using microarray analysis. Neither type I IFNs, nor TLRs, nor IFN-inducible antiviral genes were induced in imiquimod-treated FL cells. Cystatin A, a host cysteine protease inhibitor, was strongly upregulated by imiquimod and took a major part in the anti-HSV-1 activity deduced by the suppression experiment using its small interfering RNA. Upregulation of cystatin A was suggested to be mediated by antagonizing adenosine receptor A(1) and activating the protein kinase A pathway. Imiquimod, but not resiquimod, was shown to interact with adenosine receptor A(1). Imiquimod-induced anti-HSV-1 activity was observed in other cells, such as HeLa, SiHa, and CaSki cells, in a manner consistent with the cystatin A induction by imiquimod. These results indicated that imiquimod acted as an antagonist for adenosine receptor A(1) and induced a host antiviral protein, cystatin A. The process occurred independently of TLR7 and type I IFNs.

Implication of Antigenic Conversion of Helicobacter pylori Lipopolysaccharides That Involve Interaction with Surfactant Protein D

Shin-ichi Yokota, Ken-ichi Amano, Chiaki Nishitani, Shigeru Ariki, Yoshio Kuroki, Nobuhiro Fujii

INFECTION AND IMMUNITY ( AMER SOC MICROBIOLOGY ) 80 ( 8 ) 2956 - 2962 2012.08 [Refereed]

We propose two antigenic types of Helicobacter pylori lipopolysaccharides (LPS): highly antigenic epitope-carrying LPS (HA-LPS) and weakly antigenic epitope-carrying LPS (WA-LPS) based on human serum reactivity. Strains carrying WA-LPS are highly prevalent in isolates from gastric cancer patients. WA-LPS exhibits more potent biological activities compared to HA-LPS, namely, upregulation of Toll-like receptor 4 (TLR4) expression and induction of enhanced epithelial cell proliferation. The results of competitive binding assays using monosaccharides and methylglycosides, as well as binding assays using glycosidase-treated LPS, suggested that beta-linked N-acetyl-D-glucosamine and beta-linked D-galactose residues largely contributed to the highly antigenic epitope and the weakly antigenic epitope, respectively. WA-LPS exhibited greater binding activity to surfactant protein D (SP-D) in a Ca2+-dependent manner, and this interaction was inhibited by methyl-beta-D-galactoside. The biological activities of WA-LPS were markedly enhanced by the addition of SP-D. Lines of evidence suggested that removal of beta-N-acetyl-D-glucosamine residue, which comprises the highly antigenic epitope, results in exposure of the weakly antigenic epitope. The weakly antigenic epitope interacted preferentially with SP-D, and SP-D enhanced the biological activity of WA-LPS.

Clarithromycin Suppresses Human Respiratory Syncytial Virus Infection-Induced Streptococcus pneumoniae Adhesion and Cytokine Production in a Pulmonary Epithelial Cell Line

Shin-ichi Yokota, Tamaki Okabayashi, Satoshi Hirakawa, Hiroyuki Tsutsumi, Tetsuo Himi, Nobuhiro Fujii

MEDIATORS OF INFLAMMATION ( HINDAWI PUBLISHING CORPORATION ) 2012 528568 2012 [Refereed]

Human respiratory syncytial virus (RSV) sometimes causes acute and severe lower respiratory tract illness in infants and young children. RSV strongly upregulates proinflammatory cytokines and the platelet-activating factor (PAF) receptor, which is a receptor for Streptococcus pneumoniae, in the pulmonary epithelial cell line A549. Clarithromycin (CAM), which is an antimicrobial agent and is also known as an immunomodulator, significantly suppressed RSV-induced production of interleukin-6, interleukin-8, and regulated on activation, normal T-cell expressed and secreted (RANTES). CAM also suppressed RSV-induced PAF receptor expression and adhesion of fluorescein-labeled S. pneumoniae cells to A549 cells. The RSV-induced S. pneumoniae adhesion was thought to be mediated by the host cell's PAF receptor. CAM, which exhibits antimicrobial and immunomodulatory activities, was found in this study to suppress the RSV-induced adhesion of respiratory disease-causing bacteria, S. pneumoniae, to host cells. Thus, CAM might suppress immunological disorders and prevent secondary bacterial infections during RSV infection.

Prevalence of Fluoroquinolone-Resistant Escherichia coli O25:H4-ST131 (CTX-M-15-Nonproducing) Strains Isolated in Japan

Shin-ichi Yokota, Toyotaka Sato, Torahiko Okubo, Yasuo Ohkoshi, Tamaki Okabayashi, Osamu Kuwahara, Yutaka Tamura, Nobuhiro Fujii

CHEMOTHERAPY ( KARGER ) 58 ( 1 ) 52 - 59 2012 [Refereed]

Background: Fluoroquinolone-resistant and extended-spectrum p-lactamase (ESBL)-carrying multidrug-resistant Escherichia coli have become severely problematic. In particular, a lineage of multilocus sequence-type 51131 which belongs to O25:H4 and carries BBL CTX-M-15 has spread worldwide. Methods: Fluoroquinolone-resistant E. coli strains were isolated from various clinical specimens in a commercial clinical laboratory in 2008 and 2009 in Hokkaido Prefecture, Japan. Results: Among 478 clinical isolates, 112 strains (23.4%) showed levofloxacin (LVX) resistance. About 80% of the fluoroquinolone-resistant strains (88 strains) showed common features, namely O25:H4-ST131, phylogenetic group B and the same mutation pattern in quinolone resistance-determining regions. Pulsed field gel electrophoresis patterns suggested numerous lineages of O25:H4ST131. The fluoroquinolone-resistant strains, including strains of O25:H4-51-131 and other types, more frequently shared CTX-type ESBL genes than did fluoroquinolone-susceptible strains. The ESBL genes fell into the CTX-M-9 and CTX-M-2 groups. CTX-M-15 (CTX-M-1 group) was not found among any of the strains isolated in this study. Sitafloxacin showed markedly potent activity against E. coli isolates compared with LVX, ciprofloxacin and ulifloxacin. Conclusion: The most prevalent fluoroquinolone-resistant strains of E. coli isolated in Hokkaido Prefecture, Japan, are O25:H4ST131. However, similar to other areas of Japan, the 51131 clones represent distinct lineages from the general worldwide dispersal of multidrug-resistant clones which carry CTX-M-15. Copyright (C) 2012 S. Karger AG, Basel

Comparison of the serological reactivity of lipopolysaccharides from Japanese and Western strains of Helicobacter pylori to sera from H. pylori-positive humans.

Amano K, Yokota S, Monteiro MA

ISRN Microbiology 2012 162816 2012 [Refereed]

Type-III interferon, not type-I, is the predominant interferon induced by respiratory viruses in nasal epithelial cells

Tamaki Okabayashi, Takashi Kojima, Tomoyuki Masaki, Shin-ichi Yokota, Tadaatsu Imaizumi, Hiroyuki Tsutsumi, Tetsuo Himi, Nobuhiro Fujii, Norimasa Sawada

VIRUS RESEARCH ( ELSEVIER SCIENCE BV ) 160 ( 1-2 ) 360 - 366 2011.09 [Refereed]

As an innate immune response against diverse viral infections, a host induces two types of interferon (IFN), type-I (IFN-beta/alpha) and type-III (IFN-lambda). We investigated IFN inductions by respiratory viruses, including respiratory syncytial virus (RSV), measles virus and mumps virus in human nasal epithelial cells (NECs). IFN-lambda, but not IFN-beta/alpha, was induced by respiratory virus infection in primary NECs and immortalized NECs through transfection with the human telomerase reverse transcriptase gene (hTERT-NECs). In contrast, both IFN-lambda and IFN-beta/alpha were induced by RSV infection in human bronchiolar carcinoma cell line A549. Suppression of retinoic acid-inducible gene-I (RIG-I) expression using siRNA significantly reduced IFN-lambda 1 production in RSV-infected hTERT-NECs, while suppression of melanoma differentiation-associated gene 5 (MDA5) expression did not. Exogenous IFN-lambda 1 treatment suppressed RSV replication and chemokine induction in hTERT-NECs. These data indicate that IFN-lambda, but not IFN-beta/alpha, contributes to the main first line defense via RIG-I-dependent pathway against respiratory virus infection in NECs. (C) 2011 Elsevier B.V. All rights reserved.

A Fluoroquinolone-Resistant Escherichia coli Clinical Isolate without Quinolone Resistance-Determining Region Mutations Found in Japan

Toyotaka Sato, Shin-ichi Yokota, Ikuo Uchida, Torahiko Okubo, Kanako Ishihara, Nobuhiro Fujii, Yutaka Tamura

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY ( AMER SOC MICROBIOLOGY ) 55 ( 8 ) 3964 - 3965 2011.08 [Refereed]

Measles virus C protein suppresses gamma-activated factor formation and virus-induced cell growth arrest

Shin-ichi Yokota, Tamaki Okabayashi, Nobuhiro Fujii

VIROLOGY ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 414 ( 1 ) 74 - 82 2011.05 [Refereed]

Measles virus (MeV) produces two accessory proteins, V and C, from the P gene. These accessory proteins have been reported to contribute to efficient virus proliferation through the modulation of host cell events. Our previous paper described that Vero cell-adapted strains of MeV led host cells to growth arrest through the upregulation of interferon regulatory factor 1 (IRF-1), and wild strains did not. In the present study, we found that C protein expression levels varied among MeV strains in infected SiHa cells. C protein levels were inversely correlated with IRF-1 expression levels and with cell growth arrest. Forced expression of C protein released cells from growth arrest. C-deficient recombinant virus efficiently upregulated IRF-1 and caused growth arrest more efficiently than the wild-type virus. C protein preferentially bound to phosphorylated STAT1 and suppressed STAT1 dimer formation. We conclude that MeV C protein suppresses IFN-gamma signaling pathway via inhibition of phosphorylated STAT1 dimerization. (C) 2011 Elsevier Inc. All rights reserved.

フルオロキノロン耐性肺炎球菌，インフルエンザ菌に対する各種キノロン系抗菌薬の活性比較

横田伸一, 大越康雄, 藤井暢弘

日本臨床微生物学雑誌 21 ( 1 ) 17 - 24 2011 [Refereed]

Fosfomycin suppresses RS-virus-induced Streptococcus pneumoniae and Haemophilus influenzae adhesion to respiratory epithelial cells via the platelet-activating factor receptor

Shin-ichi Yokota, Tamaki Okabayashi, Yuko Yoto, Tsukasa Hori, Hiroyuki Tsutsumi, Nobuhiro Fujii

FEMS MICROBIOLOGY LETTERS ( WILEY-BLACKWELL ) 310 ( 1 ) 84 - 90 2010.09 [Refereed]

Human respiratory syncytial virus (RSV) sometimes causes acute and severe lower respiratory tract illness in infants and young children. The platelet-activating factor (PAF) receptor, which is a receptor for Streptococcus pneumoniae and Haemophilus influenzae, is upregulated by RSV infection in the pulmonary epithelial cell line A549. Fosfomycin, an antimicrobial agent, significantly suppressed PAF receptor induction by RSV infection at the mRNA and cell surface expression levels. Fosfomycin also suppressed RSV-induced adhesion of fluorescence-labeled S. pneumoniae and H. influenzae cells, as determined by flow cytometry and fluorescence microscopy. The RSV-induced bacterial adhesion was suggested to be host-PAF-receptor and bacterial-phosphocholine mediated. Fosfomycin, which has been shown to exhibit antimicrobial and immunomodulatory activities, was found here to suppress adhesion by disease-causing bacteria. Thus, fosfomycin might prevent secondary bacterial infection during RSV infection.

Acquisition of a Transposon Encoding Extended-Spectrum beta-Lactamase SHV-12 by Pseudomonas aeruginosa Isolates during the Clinical Course of a Burn Patient

Shuji Uemura, Shin-ichi Yokota, Hirotoshi Mizuno, Eiji Sakawaki, Keigo Sawamoto, Kunihiko Maekawa, Katsutoshi Tanno, Kazuhisa Mori, Yasufumi Asai, Nobuhiro Fujii

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY ( AMER SOC MICROBIOLOGY ) 54 ( 9 ) 3956 - 3959 2010.09 [Refereed]

Increased Caspase-2 Activity is Associated with Induction of Apoptosis in IFN-beta Sensitive Melanoma Cell Lines

Takafumi Kamiya, Tamaki Okabayashi, Shin-ichi Yokota, Yuji Kan, Jiro Ogino, Toshiharu Yamashita, Nobuhiro Fujii, Kowichi Jimbow

JOURNAL OF INTERFERON AND CYTOKINE RESEARCH ( MARY ANN LIEBERT INC ) 30 ( 5 ) 349 - 357 2010.05 [Refereed]

Interferon (IFN) is believed to be one of the most effective anti-melanoma agents. Specifically, IFN-beta has the ability to induce apoptosis of melanoma cells. Induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has also been suggested to have a critical role in IFN-beta-induced apoptosis. To characterize the signaling pathway involved in IFN-beta-induced apoptosis, we analyzed the biological effects of IFN-beta on the cell death and caspase activation of melanoma cells. IFN-sensitive cell lines, MM418, SK-mel-23, and SK-mel-118, showed increased apoptotic populations correlated with the activation of caspase-2 and caspase-3 by IFN-beta. IFN-beta-induced apoptosis was significantly suppressed by inhibitors for caspase-2 or caspase-3, but not by inhibitors for caspase-8 or caspase-9 in these cell lines. TRAIL expression was observed in IFN-beta-treated cells of SK-mel-23 and SK-mel-118, but not in those cells of MM418, which showed massive IFN-beta-induced apoptosis and resistance to exogenous TRAIL-mediated apoptosis. G361 was resistant to IFN-beta-induced apoptosis but sensitive to exogenous TRAIL-mediated apoptosis. Furthermore, IFN-beta pretreatment significantly increased the sensitivity against exogenous TRAIL-mediated apoptosis and activation of caspase-2 in G361. These results suggested that caspase-2 activation is commonly associated with induction of IFN-beta-induced apoptosis in IFN-beta-sensitive melanoma cells.

Pulmonary Collectins Protect Macrophages against Pore-forming Activity of Legionella pneumophila and Suppress Its Intracellular Growth

Kaku Sawada, Shigeru Ariki, Takashi Kojima, Atsushi Saito, Masami Yamazoe, Chiaki Nishitani, Takeyuki Shimizu, Motoko Takahashi, Hiroaki Mitsuzawa, Shin-ichi Yokota, Norimasa Sawada, Nobuhiro Fujii, Hiroki Takahashi, Yoshio Kuroki

JOURNAL OF BIOLOGICAL CHEMISTRY ( AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC ) 285 ( 11 ) 8434 - 8443 2010.03 [Refereed]

Pulmonary collectins, surfactant proteins A (SP-A) and D (SP-D), play important roles in innate immunity of the lung. Legionella pneumophila is a bacterial respiratory pathogen that can replicate within macrophages and causes opportunistic infections. L. pneumophila possesses cytolytic activity, resulting from insertion of pores in the macrophage membrane upon contact. We examined whether pulmonary collectins play protective roles against L. pneumophila infection. SP-A and SP-D bound to L. pneumophila and its lipopolysaccharide (LPS) and inhibited the bacterial growth in a Ca(2+)-dependent manner. The addition of LPS in the culture blocked the inhibitory effects on L. pneumophila growth by the collectins, indicating the importance of LPS-collectin interaction. When differentiated THP-1 cells were infected with L. pneumophila in the presence of SP-A and SP-D, the number of permeable cells was significantly decreased, indicating that pulmonary collectins inhibit pore-forming activity of L. pneumophila. The number of live bacteria within the macrophages on days 1-4 after infection was significantly decreased when infection was performed in the presence of pulmonary collectins. The phagocytosis experiments with the pH-sensitive dye-labeled bacteria revealed that pulmonary collectins promoted bacterial localization to an acidic compartment. In addition, SP-A and SP-D significantly increased the number of L. pneumophila co-localized with LAMP-1. These results indicate that pulmonary collectins protect macrophages against contact-dependent cytolytic activity of L. pneumophila and suppress intracellular growth of the phagocytosed bacteria. The promotion of lysosomal fusion with Legionella-containing phagosomes constitutes a likely mechanism of L. pneumophila growth suppression by the collectins.

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