• Asian Pacific Journal of Cancer Prevention
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• v.15 no.1
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• pp.265-271
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• 2014

Interleukin-7 (IL-7) is a potent anti-apoptotic cytokine that enhances immune effector cell functions and is essential for lymphocyte survival. While it known to induce differentiation and proliferation in some haematological malignancies, including certain types of leukaemias and lymphomas, little is known about its role in solid tumours, including breast cancer. In the current study, we investigated whether IL-7 could enhance the in vivo antitumor activity of tumor-reactive $CD8^+$ T cells with induction of IFN-${\gamma}$ in a murine breast cancer model. Human IL-7 cDNA was constructed into the eukaryotic expression plasmid pcDNA3.1, and then the recombinational pcDNA3.1-IL-7 was intratumorally injected in the TM40D BALB/C mouse graft model. Serum and intracellular IFN-${\gamma}$ levels were measured by ELISA and flow cytometry, respectively. $CD8^+$ T cell-mediated cytotoxicity was analyzed using the MTT method. Our results showed that IL-7 administration significantly inhibited tumor growth from day 15 after direct intratumoral injection of pcDNA3.1-IL-7. The anti-tumor effect correlated with a marked increase in the level of IFN-${\gamma}$ and breast cancer cells-specific CTL cytotoxicity. In vitro cytotoxicity assays showed that IL-7-treatment could augment cytolytic activity of $CD8^+$ T cells from tumor bearing mice, while anti-IFN-${\gamma}$ blocked the function of $CD8^+$ T cells, suggesting that IFN-${\gamma}$ mediated the cytolytic activity of $CD8^+$ T cells. Furthermore, in vivo neutralization of $CD8^+$ T lymphocytes by CD8 antibodies reversed the antitumor benefit of IL-7. Thus, we demonstrated that IL-7 exerts anti-tumor activity mainly through activating $CD8^+$ T cells and stimulating them to secrete IFN-${\gamma}$ in a murine breast tumor model. Based on these results, our study points to a potential novel way to treat breast cancer and may have important implications for clinical immunotherapy.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.8
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• pp.3117-3120
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• 2015

Objective: Interferon-${\gamma}$ (IFN-${\gamma}$) and signal transducers and activators of transcription (STATs) each play an important role in carcinogenesis associated with viral infection. Cervical cancer is almost invariably associated with infection by human papillomavirus (HPV), and previous studies suggested that dysregulation of the signal pathway involved in IFN-${\gamma}$ and STATs is associated. Our objective was to evaluate the association of SNPs in STAT2, STAT3, and IFN-${\gamma}$ with cervical cancer susceptibility in Chinese Han women in Hunan province. Materials and Methods: Genomic DNA was extracted from peripheral blood samples of 234 cervical cancer patients and 216 healthy female controls. STAT2 and STAT3 genotyping was performed using polymerase chain reaction-restriction enzyme (PCR-RE) analysis. IFN-${\gamma}$ genotyping was detected by PCR-amplification of specific allele (PASA). Results: For STAT2 rs2066807 polymorphisms, there was no significant difference of genotype distribution (P=0.827) and allele frequencies (P=0.830, OR=1.09, 95% CI: 0.51-2.31) between cases and controls. For STAT3 rs957970 polymorphisms, there was no significant difference of genotype distribution (P=0.455) and allele frequencies (P=0.560, OR=0.92, 95% CI: 0.71-1.20) between cases and controls. For IFN-${\gamma}$ +874A/T polymorphisms, there was no significant difference of genotype distribution (P=0.652) and allele frequencies (P=0.527, OR=1.12, 95% CI: 0.79-1.59) between cases and controls. Conclusion: These results suggest that polymorphisms in STAT2, STAT3 and IFN-${\gamma}$ genes are not likely to be strong predictors of cervical cancer in Han women in southern China.

• Clinical and Experimental Pediatrics
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• v.58 no.4
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• pp.129-135
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• 2015

Purpose: This study investigated the long-term clinical outcomes of patients with $p22^{phox}$-deficient chronic granulomatous disease (CGD) on Jeju Island and retrospectively evaluated the effects of interferon-gamma (IFN-${\gamma}$) prophylaxis. Methods: The medical records of 15 patients with CGD were retrospectively reviewed. The efficacy of IFN-${\gamma}$ prophylaxis was evaluated by comparing the frequency of severe infections before and after starting continuous prophylaxis with IFN-${\gamma}$. Results: At the time of the analysis, 14 patients were alive, with a median age of 14.3 years. The diagnosis of CGD was made at a median age of 2.4 years, and the median age at onset of severe infection was 0.3 years. Thirteen of the 15 patients had their first severe infection within the first year of life. The overall incidence of severe infection was 1.36 infections per patient-year; pneumonia, suppurative lymphadenitis, and skin and subcutaneous abscesses were the most common infections. Aspergillus species were the most frequently isolated microorganisms, present in 15.8% of isolates. IFN-${\gamma}$ did not significantly change the rate of severe infection. The survival rate for patients after 2 years of age was 93%; there was a prolonged survival plateau beyond the age of 2. Conclusion: Compared with cases of X-linked CGD reported in other studies, patients with CGD on Jeju Island did not show obviously different clinical manifestations, but they had a significantly higher survival rate. Further studies with a substantially longer period of observation, and with more patients under intensive surveillance are necessary to elucidate the prophylactic efficiency of IFN-${\gamma}$.

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

• YAKHAK HOEJI
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• v.45 no.5
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• pp.557-564
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• 2001

To determine effects of zinc on lipopolysaccharide (LPS)-induced production of proinflammatory cytokines and Iymphokines in tumor-bearing ICR mice, this study has been investigated. Zinc chloride (Zn) at doses of 1 mg/kg was administered orally 30 minutes before i.p. injection of LPS (8 mg/kg) 5 times for 7 days. LPS greatly increased tumor necrosis factor (TNF)-$\alpha$ and interleukin (IL)-1$\beta$, in both serum and splenic supernatants compared with those in controls. However Zn strongly decreased LPS-increased production of TNF-$\alpha$ and IL-1$\beta$ in spleenic supernatants compared with those in controls and insignificantly also reduced in serum. LPS insignificantly decreased IL-2 levels in spleenic supernatants compared with those in controls but significantly increased interferon (IFN)-${\gamma}$ levels. Zn didn't affect IL-2 production in splenic supernatants compared to controls but significantly enhanced the LPS-decreased production of IL-2. Zn significantly increased IFN-${\gamma}$ levels in splenic supernatants compared to controls and did not affect the LPS-increased production of IFN-${\gamma}$. These findings suggest that Zn may strongly attenuate the LPS-induced pathogenesis of proinflammatory cytokines in tumor-bearing state and significantly up-regulate the LPS-induced function of T cells to produce IL-2 with maintaining normally the LPS- increased levels of IFN-${\gamma}$.

• YAKHAK HOEJI
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• v.44 no.5
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• pp.448-454
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• 2000

Microglia, brain resident macrophages, play a central role in the inflammatory responses of the brain and are activated in brain injuries and several neurodegenerative diseases such as Alzheimer's and Parkinson's disease, thereby aggravating the course of these diseases. In this study, the effects of plantderived compounds such as curcumin or gingerol on the microglial activation were examined. Microglial cultures were prepared from 2~3 week mixed primary glial cultures obtained from the cerebral cortex of 1~2 day old rats and identified by immunocytochemistry using microglial-specific antibody OX-42. Microglia were activated by lipopolysaccharide (LPS) and interferon-${\gamma}$ (IFN-${\gamma}$) and the effect of curcumin or 6-gingerol on the microglial activation was examined. Specific parameters measured to monitor microglial activation were nitric oxide (NO), prostaglandin E$_2$(PGE$_2$) and tumor necrosis factor-$\alpha$ (TNF-$\alpha$) release. Curcumin (1~10 $\mu$M) inhibited NO release induced by LPS and IFN-${\gamma}$ in a dose-dependent manner whereas 6-gingerol (2~20 $\mu$M) did not have any effect on LPS/IFN-${\gamma}$-induced NO release. The levels of PGE$_2$and TNF-$\alpha$ induced by LPS and IFN-${\gamma}$ were also inhibited by 1~10 $\mu$M curcumin in a dose-dependent manner. These results showed that curcumin could modulate microglial activation.

• Journal of Embryo Transfer
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• v.28 no.1
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• pp.13-18
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• 2013

The increase in the meat quality and milk production of cows, which breed Korean Native Cow (KNC) and Holstein cow, is not improving reproductive efficiency. In this study, we examined the effect of interferon (IFN) supplementation on motility of frozen-thawed semen and pregnancy rate after artificial insemination of KNC and Holstein cow. In experiment 1, we investigated the effect of IFN-tau concentration (10,000 IU and 20,000 IU) on the percentage of total motility (TM) and progressive motility (PM) of frozen-thawed spermatozoa. In experiment 2, KNC were infused 20,000 IU IFN-tau at insemination or after insemination. In experiment 3, KNC or Holstein cow were inseminated with frozen-thawed semen and infused 20,000 IU IFN-gamma or -tau after insemination. In experiment 1, the average of TM (23.9% to 30.9%) and PM (18.5% to 21.9%) were similar between control and treatments. In experiment 2, the pregnancy rates of IFN infusing times were not different from 45.8% to 53.6%. In experiment 3, the pregnancy rates of Holstein cow infused different kinds of IFN were similar (control, IFN-gamma, IFN-tau; 42.9%, 40.5%, 48.0%). In the case of KNC, however, the pregnancy rate of control was 55.6%, which was significantly lower than that of IFN-gamma (68.9%; p<0.05). Thus, IFN is effective on the improvement of reproductive efficiency, but further study is needed.

• Advances in Traditional Medicine
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• v.8 no.2
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• pp.125-129
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• 2008

Korean Marine Plants (KMU-4, 6, 7) obtained from an herb which widely used in medicine for the treatment of a variety of pathologies. In this study, using mouse peritoneal macrophages, we have examined whether KMU-4, 6, 7 affects nitric oxide (NO) and COX-2 induced IFN-$\gamma$ and LPS and cell viability. KMU-6 inhibits IFN-$\gamma$ and LPS-induced NO. We found that KMU-6 had a little effect on COX-2 expression. These finding means that KMU-6 can be used in controlling macrophages mediated inflammatory disease. The present results indicate that KMU-6 has an inhibitory effect on the production of NO through down-regulation of COX-2 expression in LPS stimulated mouse peritoneal macrophages.

• IMMUNE NETWORK
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• v.2 no.3
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• pp.142-149
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• 2002

Background: Our previous study showed that purified protein derivative (PPD)-stimulated pleural mononuclear cells (PMC) from tuberculous pleurisy (Tbp) produced significantly more $IFN-{\gamma}$ (10- to 70-fold) after in vitro PPD stimulation than freshly isolated pleural cells from malignant pleurisy. The present study was designed to determine whether blocking the CD40-CD40 ligand (CD40L) interaction decreases $IFN-{\gamma}$ production by altering IL-12 levels. Methods: IL-12 and $IFN-{\gamma}$ production after neutralizing anti-CD40L antibody treatment was compared to the efficacy of anti-CD80, anti-CD86, and a combination of anti-CD80 and CD86 (CD80+86) monoclonal antibodies (mAb). These activities were measured by enzyme-linked immunosorbent assays (ELISAs) and reverse transcription-polymerase chain reaction (RT-PCR), after in vitro stimulation with PPO antigen (Ag). Results: Neutralization of CD80, CD86 and CD80+86 did not decrease $IFN-{\gamma}$ and IL-12 production in Tbp-PMC, whereas neutralization of CD40L significantly depressed IL-12 p40 and $IFN-{\gamma}$. In addition, neutralization of CD40L completely inhibited IL-12 p40 and $IFN-{\gamma}$ mRNA expression. Conclusion: The CD40-CD40L interaction might play a major role in IL-12 and $IFN-{\gamma}$ production in Tbp-PMC, thus contributing to protective immunity in human tuberculosis.

• IMMUNE NETWORK
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• v.2 no.1
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• pp.53-59
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• 2002

Background: Clinical observations and laboratory studies have supported an immune basis for most acquired aplastic anemias, with the majority of patients responding to immunosuppressive therapy. Fas, a member of the tumor necrosis factor (TNF) receptor superfamily is a critical downregulator of cellular immune responses. Proinflammatory cytokines like interferon gamma (IFN-${\gamma}$) and TNF-${\alpha}$ can induce Fas expression and render hematopoietic progenitor cells susceptible to Fas-induced growth suppression and apoptosis. Methods: In order to investigate the involvement of apoptosis in the pathogenesis of aplastic anemia (AA), we measured the expression of Fas antigen and caspase-3 on bone marrow (BM) mononuclear cells (MNCs) of AA in the presence or absence of IFN-${\gamma}$, TNF-${\alpha}$, or macrophage inflammatory protein 1-${\alpha}$ (MIP-$1{\alpha}$). Results: We confirmed that AA BM MNCs were more apoptotic and highly expressed Fas antigen than normal donors. Stimulation by IFN-${\gamma}$, TNF-${\alpha}$, or MIP-$1{\alpha}$ increased Fas antigen and caspase-3 expression in AA BM MNCs than BM MNCs of normal donors. Anti-Fas monoclonal antibody enhanced IFN-${\gamma}$, TNF-${\alpha}$, or MIP$1{\alpha}$ mediated caspase-3 expression in BM MNCs of normal donors. Among these three cytokines, IFN-${\gamma}$ enhanced apoptosis most strongly via Fas-caspase-3 pathway. Conclusion: These results suggest that Fas signal pathway may play a role in the pathophysiology of aplastic anemia and negative hematopoietic regulators like IFN-${\gamma}$ can induce apoptosis of bone marrow progenitors in part by Fas induction.