• Tuberculosis and Respiratory Diseases
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• v.81 no.1
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• pp.59-72
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• 2018

Background: It remains uncertain if $interferon-{\gamma}$ release assays (IGRAs) are superior to the tuberculin skin test (TST) for the diagnosis of active tuberculosis (TB) or latent tuberculosis infection (LTBI) in immunosuppressed populations including people with human immunodeficiency virus (HIV) infection. The purpose of this study was to systematically review the performance of IGRAs and the TST in people with HIV with active TB or LTBI in low and high prevalence TB countries. Methods: We searched the MEDLINE database from 1966 through to January 2017 for studies that compared results of the TST with either the commercial QuantiFERON-TB Gold in Tube (QFTGT) assay or previous assay versions, the T-SPOT.TB assay or in-house IGRAs. Data were summarized by TB prevalence. Tests for concordance and differences in proportions were undertaken as appropriate. The variation in study methodology was appraised. Results: Thirty-two studies including 4,856 HIV subjects met the search criteria. Fourteen studies compared the tests in subjects with LTBI in low TB prevalence settings. The QFTGT had a similar rate of reactivity to the TST, although the first-generation version of that assay was reactive more commonly. IGRAs were more frequently positive than the TST in HIV infected subjects with active TB. There was considerable study methodology and population heterogeneity, and generally low concordance between tests. Both the TST and IGRAs were affected by CD4 T-cell immunodeficiency. Conclusion: Our review of comparative data does not provide robust evidence to support the assertion that the IGRAs are superior to the TST when used in HIV infected subjects to diagnose either active TB or LTBI.

• Genomics & Informatics
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• v.3 no.4
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• pp.142-148
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• 2005

The immune response-related genes have been suggested to be the most favorable genes for positive selection during evolution. Comparing the entire DNA sequence of chimpanzee chromosome 22 (PTR22) with human chromosome 21 (HSA21), we have identified 15 orthologs having indel in their coding sequences. Among them, interferon-${\alpha}$ receptor-1 gene (IFNAR1), an immuneresponse-related gene, is subjected to comparative genomic analysis. Chimpanzee IFNAR1 showed the same genomic structure as human IFNAR1 (11 exons and 10 introns) except the 3 bp insertion in exon 4. The sequence alignment of IFNAR1 coding sequence indicated that 'ISPP' amino acid sequence motif is highly conserved in chimpanzee and other animals including mouse and chicken. However, the human IFNAR1 shows that one proline residue is missing in the sequence motif. The homology modeling of the IFNAR1 structures suggests that the proline deletion in human IFNAR1 leads to the formation of the following ${\alpha}$-helix, whereas two sequential prolines in chimpanzee IFNAR1 inhibit it. As a result, human IFNAR1 may adopt a characteristic structure distinct from chimpanzee IFNAR1. This human specific trait could contribute to specific immune response in the most optimized manner for humans. Further molecular biological studies on the IFNAR1 will help us to gain insights into the molecular implication of species-specific host-pathogen interaction in primate evolution.

• Tuberculosis and Respiratory Diseases
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• v.83 no.4
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• pp.283-288
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• 2020

Background: Latent tuberculosis (TB) infection among TB contacts is diagnosed using plain chest radiography and interferon-gamma release assays (IGRAs). However, plain chest radiographs often miss active TB, and the results of IGRA could fluctuate over time. The purpose of this study was to elucidate changes in the results of the serial IGRAs and in the findings of the serial submillisievert chest computed tomography (CT) scans among the close contacts of active pulmonary TB patients. Methods: Patients age 20 or older with active pulmonary TB and their close contacts were invited to participate in this study. Two types of IGRA (QuantiFERON-TB Gold In-Tube assay [QFT-GIT] and the T-SPOT.TB test [T-SPOT]) and submillisievert chest CT scanning were performed at baseline and at 3 and 12 months after enrollment. Results: In total, 19 close contacts participated in this study. One was diagnosed with active pulmonary TB and was excluded from further analysis. At baseline, four of 18 contacts (22.2%) showed positive results for QFT-GIT and T-SPOT; there were no discordant results. During the follow-up, transient and permanent positive or negative conversions and discordant results between the two types of IGRAs were observed in some patients. Among the 17 contacts who underwent submillisievert chest CT scanning, calcified nodules were identified in seven (41.2%), noncalcified nodules in 14 (82.4%), and bronchiectasis in four (23.5%). Some nodules disappeared over time. Conclusion: The results of the QFT-GIT and T-SPOT assays and the CT images may change during 1 year of observation of close contacts of the active TB patients.

• IMMUNE NETWORK
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• v.11 no.6
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• pp.358-363
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• 2011

Background: Traditionally, interferon-${\gamma}$ (IFN-${\gamma}$) was regarded as a pro-inflammatory cytokine, however, recent reports suggested role of IFN-${\gamma}$ in immune tolerance. In our previous report, we could induce tolerance to male antigen (HY) just by male islet transplantation in wild type C57BL/6 mice without any immunological intervention. We tried to investigate the influence of IFN-${\gamma}$ deficiency on tolerance induction by male islet transplantation. Methods: To examine the immunogenicity of male tissue in the absence of IFN-${\gamma}$, we transplanted male IFN-${\gamma}$ knock-out (KO) skin to female IFN-${\gamma}$ KO mice. Next, we analyzed male IFN-${\gamma}$ KO islet to streptozotocin-induced diabetic female IFN-${\gamma}$ KO mice. And, we checked the functionality of grafted islet by graft removal and insulin staining. Results: As our previous results in wild type C57BL/6 mice, female IFN-${\gamma}$ KO mice rejected male IFN-${\gamma}$ KO skin within 29 days, and did not reject male IFN-${\gamma}$ KO islet. The maintenance of normal blood glucose level was dependent on the presence of grafted male islet. And the male islet recipient did not reject 2nd challenge of male islet graft also. Conclusion: Deficiency of IFN-${\gamma}$ does not have influence on the result of male skin graft and male islet transplantation. Conclusively, male islet transplantation induced T cell tolerance is not dependent on the presence of IFN-${\gamma}$.

• Development and Reproduction
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• v.21 no.4
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• pp.371-378
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• 2017

Interferon-stimulated gene 15 (ISG15) is known to interfere with viral replication and infection by limiting the viral infection of cells. Interferon-stimulated gene 15 (ISG15) interferes with viral replication and infectivity by limiting viral infection in cells. It also plays an important role in the immune response. In this study, tissue-specific expression of ISG15 in healthy rock bream samples and spatial and temporal expression analysis of rock bream ISG15 (RbISG15) were performed following rock bream iridovirus (RSIV) infection. RbISG15 expression was significantly higher in the eye, gill, intestine, kidney, liver, muscle, spleen, and stomach, but low in the brain. There were particularly high levels of expression in the liver and muscle. RbISG15 expression was also examined in several tissues and at various times following RSIV infection. ISG15 expression increased within 3 h in the whole body and decreased at 24 h after infection. In addition, temporal expression of several tissues following RSIV infection showed a similar pattern in the muscle, kidney, and spleen, increasing at 3 h and decreasing at 72 h. These results suggest that ISG15 plays an important role in the immune response of rock bream. Overall, this study characterizes the response of RbISG15 following RSIV infection.

• Journal of fish pathology
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• v.23 no.2
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• pp.177-187
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• 2010

The Interferon stimulated gene 15 (ISG15) is strongly induced in many cell types by IFNs, viral infections, and double-stranded RNA (poly I:C). The ISG15 homologue cDNA was isolated from the rock bream LPS stimulated leukocyte cDNA library. The rock bream ISG15 homologue was found to consist of 833 bp encoding 157 amino acid residues. Compared with other known ISG15 peptide sequences, the most conserved regions of the rock bream ISG15 peptide were found to be the tandem ubiquitin-like domains and a C-terminal LRLRGG conjugating motif, characteristic of mammalian and non-mammalian ISG15 proteins. Phylogenetic analysis based on the deduced amino acid sequence revealed a homologous relationship between the ISG15 sequence of rock bream and that of Atlantic salmon, Atlantic cod, northern snake head, black rockfish and olive flounder. The expression of the rock bream ISG15 molecule was induced in the peripheral blood leukocytes (PBLs) from 1 to 24 h following poly I:C stimulation, with a peak at 3 h post-stimulation. The rock bream ISG15 gene was predominantly expressed in the PBLs, spleen and gill.

• BMB Reports
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• v.52 no.5
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• pp.336-341
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• 2019

The cGAS-STING pathway plays an important role in pathogen-induced activation of the innate immune response. The 29-kDa amino-terminal fibronectin fragment (29-kDa FN-f) found predominantly in the synovial fluid of osteoarthritis (OA) patients increases the expression of catabolic factors via the toll-like receptor-2 (TLR-2) signaling pathway. In this study, we investigated whether 29-kDa FN-f induces inflammatory responses via the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) pathway in human primary chondrocytes. The levels of cGAS and STING were elevated in OA cartilage compared with normal cartilage. Long-term treatment of chondrocytes with 29-kDa FN-f activated the cGAS/STING pathway together with the increased level of gamma-H2AX, a marker of DNA breaks. In addition, the expression of pro-inflammatory cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF-2), granulocyte colony-stimulating factor (G-CSF/CSF-3), and type I interferon ($IFN-{\alpha}$), was increased more than 100-fold in 29-kDa FN-f-treated chondrocytes. However, knockdown of cGAS and STING suppressed 29-kDa FN-f-induced expression of GM-CSF, G-CSF, and $IFN-{\alpha}$ together with the decreased activation of TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), and inhibitor protein ${\kappa}B{\alpha}$ ($I{\kappa}B{\alpha}$). Furthermore, NOD2 or TLR-2 knockdown suppressed the expression of GM-CSF, G-CSF, and $IFN-{\alpha}$ as well as decreased the activation of the cGAS/STING pathway in 29-kDa FN-f-treated chondrocytes. These data demonstrate that the cGAS/STING/TBK1/IRF3 pathway plays a critical role in 29-kDa FN-f-induced expression of pro-inflammatory cytokines.

• Biomolecules & Therapeutics
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• v.31 no.1
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• pp.27-39
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• 2023

Extensive research supported the therapeutic potential of curcumin, a naturally occurring compound, as a promising cytokine-suppressive anti-inflammatory drug. This study aimed to investigate the synergistic anti-inflammatory and anti-cytokine activities by combining 6-shogaol and 10-shogaol to curcumin, and associated mechanisms in modulating lipopolysaccharides and interferon-γ-induced proinflammatory signaling pathways. Our results showed that the combination of 6-shogaol-10-shogaolcurcumin synergistically reduced the production of nitric oxide, inducible nitric oxide synthase, tumor necrosis factor and interlukin-6 in lipopolysaccharides and interferon-γ-induced RAW 264.7 and THP-1 cells assessed by the combination index model. 6-shogaol-10-shogaol-curcumin also showed greater inhibition of cytokine profiling compared to that of 6-shogaol-10-shogaol or curcumin alone. The synergistic anti-inflammatory activity was associated with supressed NFκB translocation and downregulated TLR4-TRAF6-MAPK signaling pathway. In addition, SC also inhibited microRNA-155 expression which may be relevant to the inhibited NFκB translocation. Although 6-shogaol-10-shogaol-curcumin synergistically increased Nrf2 activity, the anti-inflammatory mechanism appeared to be independent from the induction of Nrf2. 6-shogaol-10-shogaol-curcumin provides a more potent therapeutic agent than curcumin alone in synergistically inhibiting lipopolysaccharides and interferon-γ induced proinflammatory mediators and cytokine array in macrophages. The action was mediated by the downregulation of TLR4/TRAF6/MAPK pathway and NFκB translocation.

• BMB Reports
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• v.56 no.5
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• pp.314-319
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• 2023

Sepsis is a life-threatening multi-organ dysfunction with high mortality caused by the body's improper response to microbial infection. No new effective therapy has emerged that can adequately treat patients with sepsis. We previously demonstrated that interferon-β (IFN-β) protects against sepsis via sirtuin 1-(SIRT1)-mediated immunosuppression. Another study also reported its significant protective effect against acute respiratory distress syndrome, a complication of severe sepsis, in human patients. However, the IFN-β effect cannot solely be explained by SIRT1-mediated immunosuppression, since sepsis induces immunosuppression in patients. Here, we show that IFN-β, in combination with nicotinamide riboside (NR), alleviates sepsis by blocking endothelial damage via SIRT1 activation. IFN-β plus NR protected against cecal ligation puncture-(CLP)-induced sepsis in wild-type mice, but not in endothelial cell-specific Sirt1 knockout (EC-Sirt1 KO) mice. IFN-β upregulated SIRT1 protein expression in endothelial cells in a protein synthesis-independent manner. IFN-β plus NR reduced the CLP-induced increase in in vivo endothelial permeability in wild-type, but not EC-Sirt1 KO mice. IFN-β plus NR suppressed lipopolysaccharide-induced up-regulation of heparinase 1, but the effect was abolished by Sirt1 knockdown in endothelial cells. Our results suggest that IFN-β plus NR protects against endothelial damage during sepsis via activation of the SIRT1/heparinase 1 pathway.

• Clinical and Experimental Pediatrics
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• v.48 no.1
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• pp.55-62
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• 2005

Purpose : We compared the therapeutic efficacy of lamivudine and alpha-interferon in children with chronic hepatitis B two years after the initiation of treatment, so that we could verify the safety and long term efficacy of lamivudine in children. Methods : We prospectively studied 44 children(32 male and 12 female; age, 1-18 years, mean, 9 years) treated for chronic hepatitis B from September 1996 to June 2004 in Kyungpook National University Hospital in Korea. Twenty three children were treated with interferon, and 21 with lamivudine. Treatment efficacy was defined as the normalization of ALT and hepatitis B virus(HBV) DNA levels, loss of HBsAg and HBeAg seroconversion at two years after the initiation of treatment. Results : Among the 23 children treated with interferon, the ALT level normalized in 10 children(43 %) and HBV DNA was undetectable in 12 children(52%). HBsAg was undetectable in one child (4 %) and HBeAg seroconversion occurred in nine children(39%) two years after the initiation of treatment. In comparison, among the 21 children treated with lamivudine, ALT normalized in 20 children (95%), HBV DNA in 19(90%), HBsAg in 5(24%), and HBeAg seroconversion occurred in 13(62%). Above all, in the lamivudine treated group under the age of seven, HBeAg and HBsAg seroconversion occurred in six(75%) and five(63%) out of the eight children respectively, which showed superior HBsAg seroconversion rate if treated in preschool aged children. Conclusion : We believe that the therapeutic efficacy of lamivudine in children with chronic hepatitis B could be better than interferon with fewer side effects, especially in preschool aged children.