• Tuberculosis and Respiratory Diseases
• /
• v.52 no.5
• /
• pp.497-505
• /
• 2002

Background : INF-${\gamma}$ plays an important role in the host response to a mycobacterial infection. A complete IFN-${\gamma}$ receptor 1 deficiency is a life threatening condition because it renders patients highly susceptible to a mycobacterial infection. Several mutations in the IFN-${\gamma}$ receptor and STAT1 gene have been identified in the rare mycobacterial infections. These mutations have partial function of the IFN-${\gamma}$ receptor and similar pathologic features to clinical tuberculosis. Materials and Methods : The function of the IFN-${\gamma}$ receptor was evaluated in the patients with clinical tuberculosis. In addition, the DNA coding sequence of the IFNgR1 and STAT1 gene was also analyzed in disseminated tuberculosis patients who might have a defective IFN-${\gamma}$ receptor. Results : The cell surface expression levels of HLA-DR and CD64 in the PMBC after being stimulation with IFN-${\gamma}$ (100IU/ml, 1000IU/ml) were increased in both controls and patients. However, the rate of increase in both groups was similar. The production of TNF-${\alpha}$ in the response to stimulation with LPS was higher in the both groups ($850.7{\pm}687.8$ vs. $836.7{\pm}564.3$ pg/ml). Pretreatment with IFN-${\gamma}$ prior to LPS stimulation resulted in further increase in TNF-${\alpha}$ production between both groups ($2203.5{\pm}242.5$ vs. $2227.5{\pm}560.4$ pg/ml). However, the rate of the increase in TNF-${\alpha}$ production in the both groups was similar. The known mutations in the IFNgR1 and STAT1 coding sequences were not found in the genomic DNA of patients with disseminated tuberculosis. Conclusion : The functional and genetic defects of the IFN-${\gamma}$ receptor were not identified in clinical tuberculosis. This suggests the defective IFN-${\gamma}$ receptor that predispoe patients to a BCG or NTM infection can not alone account for the cases of clinical tuberculosis.

• Tuberculosis and Respiratory Diseases
• /
• v.47 no.3
• /
• pp.304-310
• /
• 1999

Background: IFN-$\gamma$ plays an important role in host response to intracellular organisms such as mycobacterium. Human infection with mycobacterium leads to a wide variety of outcomes, ranging from asymptomatic infection to widespread and rapidly fatal disease. Recent reports suggest that alteration of the function of IFN-$\gamma$ caused by a defective IFN-$\gamma$ receptor gene can explain different host response to mycobacterium. In this study, we investigated the role of IFN-$\gamma$ in the development of chronic refractory tuberculosis. Methods: The LPS-induced TNF-$\alpha$ production with or without IFN-$\gamma$ priming was compared by using monocytes taken from recently diagnosed tuberculosis, chronic refractory tuberculosis patients and controls. And the IFN-$\gamma$ receptor was measured by indirect fluorescent antibody technique to know whether change in the priming effect of IFN-$\gamma$ is related to IFN-$\gamma$ receptor deficiency or not. Results: The ratio of TNF-$\alpha$ produced in response to stimulation with INF-$\gamma$ and LPS to LPS alone was $13.5{\pm}7.6$ in controls, $10.8{\pm}6.4$ in recently diagnosed tuberculosis patients and $6.7{\pm}3.9$ in chronic refractory tuberculosis patients. The priming effect of IFN-$\gamma$ significantly decreased in chronic refractory tuberculosis patients compared with that in controls(p=0.002). However, IFN-$\gamma$ receptor deficiency was detected in one of chronic refractory tuberculosis patients. Conclusion: The decrease of the priming effect of IFN-$\gamma$ may play an important role in the development of chronic refractory tuberculosis, and in some patients, this may be related to the IFN-$\gamma$ receptor deficiency.

• Tuberculosis and Respiratory Diseases
• /
• v.58 no.1
• /
• pp.11-17
• /
• 2005

Background : Interferon-gamma ($IFN-{\gamma}$) is essential in the immune response to mycobacterial infections, and a complete or partial deficiency in the $IFN-{\gamma}$ receptor 1 ($IFN{\gamma}R1$) or the $IFN-{\gamma}$ receptor 2 ($IFN{\gamma}R2$) have been reported to confer susceptibility to a disseminated infection with nontuberculous mycobacteria. However, similar mutations in the $IFN-{\gamma}$ receptor have not been specifically examined in the patients with clinical tuberculosis. Methods : This study searched for mutations in the $IFN-{\gamma}$ receptor gene that resulted in a partial $IFN-{\gamma}$ receptor deficiency in six patients with disseminated tuberculosis. The previously identified $IFN{\gamma}R1$ and $IFN{\gamma}R2$ coding regions were sequenced after amplification. Results : There was no partial $IFN{\gamma}R1$ deficiency including a homozygous recessive missense mutation causing an amino-acid substitution in the extracellular domain of the receptor (I87T) and a hotspot for small deletions (818delT, 818del4, 818insA) found in any of the patients. In addition, a partial $IFN{\gamma}R2$ deficiency of the homozygous missense mutation (R114C) was not found in any of the patients. Conclusion : Genetic defects causing a partial $IFN-{\gamma}$ receptor deficiency were not identified in our patients with disseminated tuberculosis.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.18
• /
• pp.7995-8001
• /
• 2014

Interferon-gamma (IFN-${\gamma}$) has been used to treat various malignant tumors. However, the molecular mechanisms underlying the direct anti-proliferative activity of IFN-${\gamma}$ are poorly understood. In the present study, we examined the in vitro antitumor activity of IFN-${\gamma}$ on two human non-small-cell lung carcinoma (NSCLC) cell lines, H322M and H226. Our findings indicated that IFN-${\gamma}$ treatment caused a time-dependent reduction in cell viability and induced apoptosis through a FADD-mediated caspase-8/tBid/mitochondria-dependent pathway in both cell lines. Notably, we also postulated that IFN-${\gamma}$ increased indoleamine 2,3-dioxygenase (IDO) expression and enzymatic activity in H322M and H226 cells. In addition, inhibition of IDO activity by the IDO inhibitor 1-MT or tryptophan significantly reduced IFN-${\gamma}$-induced apoptosis and death receptor 5 (DR5) expression, which suggests that IDO enzymatic activity plays an important role in the anti-NSCLC cancer effect of IFN-${\gamma}$. These results provide new mechanistic insights into interferon-${\gamma}$ antitumor activity and further support IFN-${\gamma}$ as a potential therapeutic adjuvant for the treatment of NCSLC.

• Clinical and Experimental Pediatrics
• /
• v.46 no.7
• /
• pp.702-709
• /
• 2003

Purpose : $IFN{\gamma}$ sentitizes many tumor cells to $TNF{\alpha}$ and FASL-mediated apoptosis by enhancing the expression of TNF or FAS/CD95 receptor and modulating the activation of caspase and Bcl-2 family. It has been reported that $IFN{\gamma}$ and $TNF{\alpha}$ synergistically caused differentiation and growth inhibition of neuroblastoma cells. Even though some neuroblastoma cell express FASR/FASL on the cell surface, they could not induce apoptosis by ligation of the FAS/CD95 receptor. But the treatment of $IFN{\gamma}$ is reported to induce apoptosis in some neuroblastoma cell lines through the CD95/CD95L autocrine circuit. In this study, we examined whether $IFN{\gamma}$ could affect $TNF{\alpha}$ and agonistic FAS/CD95 antibody(CH-11)-induced apoptosis against neuroblastoma cell lines that had shown diverse drug sensitivity and resistance. Methods : CHLA-15, CHLA-90 and LA-N-2 neuroblastoma cells were cultured in IMDM and treated with recombinant $IFN{\gamma}$, $TNF{\alpha}$ and CH-11 antibody. Cell viability was measured by DIMSCAN with a fluorescent calcein-AM. Apoptosis was analyzed through flow cytometry using Annexin V-PE and 7-ADD staining and confirmed by pancaspase and caspase-8 blocking experiments. The expression of TNF RI and FAS/CD95 receptor was evaluated by flow cytometry using the corresponding antibody and PE-conjugated secondary antibody. Results : $IFN{\gamma}$ or $TNF{\alpha}$ alone had no demonstrable cytotoxic effects, whereas both cytokines in combination induced apoptosis synergistically in CHLA-15 and CHLA-90 cells. Although there was no cytotoxicity with the ligation of CH-11 alone in CHLA-90 cells, pretreatment of $IFN{\gamma}$ increased the sensitivity of CH-11-mediated apoptosis. The expression of TNFRI and FAS/CD95R were non-specifically enhanced after treatment of $IFN{\gamma}$ without relation to sensitivity to $TNF{\alpha}$ and CH-11. This finding suggest up-regulation of both receptors may contribute to sensitization of $TNF{\alpha}$ and CH-11-mediated apoptosis by $IFN{\gamma}$ in only sensitive cell lines. Conclusion : $IFN{\gamma}$ induced sensitization of $TNF{\alpha}$ and agonistic FAS/CD95 antibody-mediated apoptosis on some neuroblastoma cells through up-regulation of TNFRI and FAS/CD95 receptor.

• Animal cells and systems
• /
• v.8 no.2
• /
• pp.117-123
• /
• 2004

The purpose of this study was to analyze inhibitory effects of anti-4-1BB monoclonal antibody on melanoma metastasis The 4-1BB (CD137) T cell molecule is a member of the TNF receptor family and its activation by either 4-1BB ligand or antibody induces T cell activation and growth. In the present study, administration of anti-4-1BB mAb induced inhibition of melanoma metastasis. Agonistic anti-4-1BB mAb induced not only CD$8^+$4-1BBT cells but also CD$8^+$IFN-${\gamma}$$^{+}$ T cell population. In the presence of anti-CD3 antibody, lymphocytes produced high levels of IFN-${\gamma}$ and low levels of IL-4 in anti-4-1BB mAb treated group. Exposure of melanoma cells to IFN-${\gamma}$ induced expression of MHC-I molecules. Thus, the increase in number of CD$8^+$T cells and enhanced MHC-I expression on B16F10 cells by augmented IFN-${\gamma}$ production in response to anti-4-1BB mAb may result in suppression of tumor growth and metastasis.s.

• CELLMED
• /
• v.2 no.3
• /
• pp.27.1-27.6
• /
• 2012

Red ginseng, which has a variety of biological and pharmacological activities including antioxidant, anti-inflammatory, antimutagenic and anticarcinogenic effects, has been used for thousands of years as a general tonic in traditional oriental medicine. Here, we tested the immune regulatory activities of hydrolyzed red ginseng by malted barley (HRG) on the expressions of receptor interacting proteins (Rip) 2 and $I{\kappa}B$ kinase-beta (IKK-${\beta}$) in mouse peritoneal macrophages. We show that HRG increased the activations of Rip 2 and IKK-${\beta}$ for the first time. When HRG was used in combination with recombinant interferon-${\gamma}$ (rIFN-${\gamma}$), there was a marked cooperative induction of nitric oxide (NO) production. The increased expression of inducible NO synthase from rIFN-${\gamma}$ plus HRG-stimulated cells was almost completely inhibited by pre-treatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor-${\kappa}B$ (NF-${\kappa}B$). In addition, the treatment of peritoneal macrophages with rIFN-${\gamma}$ plus HRG caused significant increases in tumor necrosis factor (TNF)-${\alpha}$ mRNA expression and production. Because NO and TNF-${\alpha}$ play an important role in the immune function and host defense, HRG treatment can modulate several aspects of the host defense mechanisms as a result of the stimulations of the inducible nitric oxide synthase and NF-${\kappa}B$. In conclusion, our findings demonstrate that HRG increases the productions of NO and TNF-${\alpha}$ from rIFN-${\gamma}$-primed macrophages and suggest that Rip2/IKK-${\beta}$ plays a critical role in mediating these immune regulatory effects of HRG.

• Journal of the Korean Society of Food Science and Nutrition
• /
• v.33 no.7
• /
• pp.1085-1091
• /
• 2004

Bu-Zhong-Yi-Qi- Tang extracts is a traditional oriental medicine in a mixture type exhibiting strong anti-bacterial, analgesic, and chemopreventive activities. In this study, we have evaluated effects of the total and polysaccharide fraction of Bu-Zhong-Yi-Qi- Tang extracts on the T cell proliferation, cytokine production, and induction of IL-2 receptor and MHC class n. For this experiment, we established CD4$^{＋}$ CD8$^{[-10]}$ T cell line producing IL-2 and IFN-${\gamma}$ when stimulated with ovalbumin antigen in the presence of antigen presenting cells. The significant effect of Bu-Zhong-Yi-Qi-Tang on antigen-induced T cell proliferation in the presence of antigen presenting cells was observed. The proliferation and IFN-${\gamma}$ production of T cells was increased in a dose dependent manner, and expression of IL-2 receptor on T cells and MHC class n molecule on antigen presenting cells was also induced in the presence of Bu-Zhong-Yi-Qi-Tang polysaccharide fraction. It was demonstrated that polysaccharide fraction of Bu-Zhong-Yi-Qi-Tang stimulates the antigen-induced T cell proliferation and the production of IFN-${\gamma}$ possibly through the increase of IL-2 receptor and MHC class n expression. Therefore Bu-Zhong-Yi-Qi-Tang can be regarded as a natural and useful immunomodulator having a relatively nonotoxic property. Further studies are needed to better characterize the nature of Bu-Zhong- Yi-Qi-Tang extract.

• Development and Reproduction
• /
• v.20 no.4
• /
• pp.315-329
• /
• 2016

Fas ligand (FasL) and its receptor Fas have been implicated in granulosa cell apoptosis during follicular atresia. Although interferon-gamma (IFN-${\gamma}$) is believed to be involved in the regulation Fas expression in differentiated granulosa or granulosa-luteal cells, the expression of this cytokine and its role in the regulation of the granulosa cell Fas/FasL system and apoptosis during follicular maturation have not been thoroughly investigated. In the present study, we have examined the presence of IFN-${\gamma}$ in ovarian follicles at different stage of development by immunohistochemistry and related their relative intensities with follicular expression of Fas and FasL, and with differences in granulosa cell sensitivity to Fas activation by exogenous agonistic Anti-Fas monoclonal antibody (Fas mAb). Although IFN-${\gamma}$ immunostaining was detectable in oocyte and granulosa cells in antral follicles, most intense immunoreactivity for the cytokine was observed in these cells of preantral follicles. Intense immunoreactivity for IFN-${\gamma}$ was most evident in granulosa cells of atretic early antral follicles where increased Fas and FasL expression and apoptosis were also observed. Whereas low concentrations of IFN-${\gamma}$ (10-100 U/mL) significantly increased Fas expression in undifferentiated granulosa cells (from preantral or very early antral follicles) in vitro, very higher concentrations (${\geq}1,000U/mL$) were required to up-regulate of Fas in differentiated cells isolated from eCG-primed (antral) follicles. Addition of agonistic Fas mAb to cultures of granulosa cells at the two stages of differentiation and pretreated with IFN-${\gamma}$ (100 U/mL) elicited morphological and biochemical apoptotic features which were more prominent in cells not previously exposed to the gonadotropin in vivo. These findings suggested that IFN-${\gamma}$ is an important physiologic intra-ovarian regulator of follicular atresia and plays a pivotal role in regulation of expression of Fas receptor and subsequent apoptotic response in undifferentiated (or poorly differentiated) granulosa cells at an early (penultimate) stage of follicular development.

• Genomics & Informatics
• /
• v.4 no.2
• /
• pp.57-64
• /
• 2006

We identified differentially expressed genes in RAW264.7 cells in response to single and double ligand treatments (LPS, $IFN{\gamma}$, 2MA, LPS plus $IFN{\gamma}$, and LPS plus 2MA). The majority of the regulated transcripts responded additively to dual ligand treatment. However, a significant fraction responded in a non-additive fashion. Several cytokines showing non-additive transcriptional responses to dual ligand treatment also showed non-additive protein production/secretion responses in separately performed experiments. Many of the genes with non-additive responses to LPS plus 2MA showed enhanced responses and encoded pro-inflammatory proteins. LPS plus $IFN{\gamma}$ appeared to induce both non-additive enhancement and non-additive attenuation of gene expression. The affected genes were associated with a variety of biological functions. These experiments reveal both dependent and independent regulatory pathways and point out the specific nature of the regulatory interactions.