인진청간탕(茵蔯淸肝湯)이 HepG2 cell의 인터페론 신호전달계에 미치는 영향

이종훈,김영철,이장훈,우홍정,Yi, Jong-Hoon,Kim, Young-Chul,Lee, Jang-Hoon,Woo, Hong-Jung 대한한방내과학회 2005 대한한방내과학회지 Vol.26 No.1

Objectives/Methods : To analyze the effect of Injinchunggantang(IJCGT) to Interferon-${\alpha}/{\beta}$ signal transmission system in HepG2 cells, HepG2 Cell were treated with IJCGT. Also, revelation of MxA, 2'5'-OAS mRNA leaded by Interferon-${\alpha}/{\beta}$ and revelation and activation of Jak1, TYK1, and STAT 1, all main signal transmission factors, were analyzed. Results : The analysis resulted in the following 1. With interferon ${\alpha}/{\beta}$ there was no affect cell propagation of Hep G2 cells. With IJCGT alone, cell propagation of HepG2 was promoted, and cell propagation control function was recovered. 2. With interferon ${\alpha}/{\beta}$ cell death was unaffected. With IJCGT apoptosis of HepG2 cell was restrained, and the cell's reaction to interferon was unaffected. 3. With interferon ${\alpha}/{\beta}$ treatment mRNA revelation of MxA and 2'5'-OAS was induced. When HepG2 cells were injected with IJCGT without interferon ${\alpha}/{\beta}$ treatment, mRNA revelation of MxA and 2'5'-OAS increased in proportion to the treatment density. With pre-treatment of IJCGT, leaded with interferon ${\alpha}/{\beta}$, promoted revelation of MxA, 2'5' -OAS mRNA. 4. Though mRNA revelation of lakl, TYK1 and STAT1 was unaffected with IJCGT, activation of STAT1 was promoted with an increase of phosphorylation of STAT1 protein. With pre-treatment of IJCGT, Jak1, TYK2, STAT1 phosphorylation, leaded with interferon, strengthened. 5. TNF-a, IL-1b and LPS present, revelation of MxA and 2'5'-OAS mRNA leaded by interferon was restrained when HepG2 cells were treated with IJCGT, and the interferon signal transmission system restraint action leaded by inflammatory cytokines was moderated. Conclusion : These results support a role for IJGCT in promotion of anti-virus action through maintainance of the liver's sensibility toward interferon. A clinical study of an interferon treated patient treated also with IJGCT is needed to determine its efficacy.

인터페론 치료에 반응이 없었던 소아의 만성 B형 간염에 대한 라미부딘의 치료 효과

연규민,김혜영,박재홍,Yeon, Gyu-Min,Kim, Hye-Young,Park, Jae-Hong 대한소아소화기영양학회 2008 Pediatric gastroenterology, hepatology & nutrition Vol.11 No.2

Purpose: Interferon is a widely used treatment for chronic hepatitis B in children. However, additional treatment options are needed because more than 50% of hepatitis B patients are unresponsive to interferon. Although lamivudine is widely used to treat hepatitis B, there are few studies on the effect of lamivudine in hepatitis B patients unresponsive to interferon. Methods: Eight interferon unresponsive patients (6 males and 2 females) were treated with lamivudine (3 mg/kg/day, maximum 100 mg/day) from 6~12 months after interferon treatment was discontinued among 33 children with chronic hepatitis B. They were treated with interferon (interferon ${\alpha}$-2b, 10 MU/$m^2$ or pegylated interferon $1.5{\mu}g/kg$) for 6 months from January 2000 to December 2007 at the Pusan National University Hospital. The medical records were analyzed retrospectively. Results: The age at treatment with interferon and lamivudine was 4.9${\pm}$3.1 and 6.1${\pm}$3.2 years, respectively. The serum ALT level before treatment with interferon was 148.1${\pm}$105.8 IU/L and the log HBV-DNA PCR mean value was 6.95${\pm}$0.70 copies/mL. The serum ALT level after treatment with interferon was 143.1${\pm}$90.4 IU/L and the log HBV-DNA mean PCR value was 6.46${\pm}$2.08. HBeAg negativization occurred in 2 patients. For all patients, normalization of the serum ALT levels and HBeAg seroconversion (except 2 patients with HBeAg negativization) occurred at 7.4${\pm}$2.1 and 7.9${\pm}$2.1 months respectively after lamivudine treatment. The HBV-DNA PCR became negative in 7 patients (87.5%) at 2.4${\pm}$2.8 months. Complete response was achieved in 7 patients and no recurrence was observed in 2 patients for 3 years after the completion of treatment. Five patients are still under treatment for a mean treatment duration of 24.4${\pm}$9.1 months. In one patient, viral breakthrough occurred and the treatment was stopped. Conclusion: The number of patients was small, however, lamivudine treatment in patients with chronic hepatitis B who were unresponsive to interferon was highly effective.

소화기암 세포주에 대한 Interferon 의 항암제 세포독성 증강 효과

김성철(Sung Chul Kim),길준영(Jun Young Kil),전의건(Eui Gun Chun),윤환중(Hwan Jung Yun),조덕연(Deog Yeon Jo),김삼용(Sam Yong Kim),김영건(Young Kun Kim) 대한내과학회 1992 대한내과학회지 Vol.43 No.5

Background: 1nterferons (IFN) have antiproliferative activity and immune moduiatory function. Interferons and cytotoxic drugs have different mechanism of action on cancer cells. To investigate the interaction of interferons with cytotoxic drugs, we treated human gastrointestinal cancer cells with combinations of anti- cancer drugs and interferons. Methods: Using the colorimetric [3-(4, 5-dimethlyth- iazo1-2-yl)-2, 5-diphenyltetraxolium bromide] (MTT) assay, we evaluated the chemosensitivity of anticancer drugs (5-fluorouracil, adriamycin), and the inhibitory effects of alpha interferon and gamma interferon, and the cytotoxic effects of the combination of interferons and anticancer drugs against the human gastric cancer cell line SNU-5 and the colon cancer cell line SNU-C. Results : Both 5-FU and adriamycin produced dosedependent inhibition of cancer cell growth; the alpha interferon and the gamma interferon had 12% and 18% inhibitory effects against SNU-5 cells respectively, and they showed 29% and 30% inhibitory effects against SNU-C1 cells respectively. Cytotoxicity of anticancer drugs was markedly augmented by the addition of alpha or gamma interferons. The II4 values of 5-FU and adriamycin decreased to 1/ 37 and 1/33, respectively, when alpha interferon was added to these drugs, and ID50 values of 5-FU and adriamycin decreased to 1/7 and 1/5.4, respectively, when the gamma interferon was added. Conclusions: The results indicate that interferons, when used concomitantly with the cytotoxic drug 5-FU or adriamycin, can augment the cytotoxicity of the latter drugs. A clinical trial incorporating interferons with anticancer drugs in gastrointestinal malignancies should be warranted.

Interferon-γ가 치주인대세포의 Collagen 및 Fibronectin의 합성과 Alkaline Phosphatase 활성에 미치는 영향

김광석(Gwang-Seok Kim),성재현(Jae-Hyun Sung),최제용(Je-Yong Choi),류현모(Hyun-Mo Ryou) 대한치과교정학회 1993 대한치과교정학회지 Vol.23 No.2

Interferon-γ has been suggested as a cytokine of connective tissue stabilizer. In addition, it has also been demonstrated that this cytokine inhibited bone remodeling activities of the bone derived cells. In order to illuminate the effects of this cytokine in orthodontic force induced bone remodeling, it was administered to primary cultured periodontal ligament cells which have been known to have some osteoblast like characteristics. Interferon-γ slightly decreased [^³H]thymidine incorporation rate without a significant change in the total cellular DNA content up to 1000 U/ml, which meant these doses were not cytotoxic to the cell. Total protein synthesis was not influenced by various concentration of interferon-γ whether it was determined by the [^³H]proline incorporation rate or by the Lowry smethod. The effect of interferon-γ on the individual protein was, however, differential, ie, it increased [^³H]proline incorporation into the noncollagenous protein marginally, while it decreased [^³H]proline incorporation into the collagen, so that it caused dose-dependent suppression of the relative collagen synthesis. On the contrary, the fibronectin synthesis determined by the ELISA was increased by 1000 U/ml of interferon-γ. The differential effects of the interferon-γ on the collagen and fibronectin synthesis exhibited not only their protein level but also the steady state mRNA level. Interferon-γ decreased steady state level of α1(I) procollagen mRNA significantly, while showing no significant changes in the fibronectin mRNA level. In addition to this, it was also found that indomethacin did not affect on the interferon-γ induced collagen decrease in this cell, which meant prostaglandins were not involved in the process of interferon-γ induced collagen decrease. So it can be concluded that the incubation of periodontal ligament cells with 1000 U/ml of interferon-γ for 24 hr showed differential effects on the type I collagen and fibronectin gene expression. The decrease in relative collagen synthesis in the protein level was related with decrease in the steady state level of mRNA, while the increase in the fibronectin synthesis in the protein level was not correlated with the mRNA level.

만성 C형 간염 환자에서 Interferon-${\alpha}$를 투여중 발생한 간질성 폐렴 1예

윤종구,안중현,고승현,이현승,권순석,김영균,문화식,박성학,송정섭,Yoon, Jong Goo,Ahn, Joong Hyun,Ko, Seung Hyeon,Lee, Hyun Seoung,Kwon, Soon Seog,Kim, Young Kyoon,Moon, Hwa Sik,Park, Sung Hak,Song, Jeong Sup 대한결핵및호흡기학회 1996 Tuberculosis and Respiratory Diseases Vol.43 No.4

Interstitial pneumonitis associated with interferon alpha therapy for chronic hepatitis C was first describe6 in 1994 by Kazoo et al In Japan. The mechanism of interstitial pneumonitis developed by interferon alpha was still unknown but immunologic, allergic of direct lung toxicity were suggested. We experienced a case of interstitial pneumonitis developed during interferon alpha therapy for chronic hepatitis C in a 52-year-old male patient. He was treated with 6 million units of interferon alpha intramuscularly 3 times per week for 4 weeks and noted progressive dyspnea and cough. These symptoms were subsided after 6 weeks' discontinuation of interferon alpha therapy. And so, he was retreated with 3 million units of interferon alpha 3 times per week for 8 weeks and felt dyspnea again. He was admitted to our hospital for further evaluation of progressive dyspnea. Arterial blood gas(ABG) values were $PaO_2$ 90.7 mmHg and $PaCO_2$ 31.9 mmHg, and antinuclear antibody(ANA) was negative. A chest X-ray film revealed diffuse reticulo-nodular shadows in bilateral lung fields, suggesting a diagnosis of interstitial pneumonitis. A marked increase in lymphocyte count and suppressor T cell were observed in bronchoalveolar lavage(BAL) fluid. Lymphocyte stimulation test with interferon alpha was positive. Interstitial pneumonitis was confirmed by transbronchial lung biopsy. After discontinuation of interferon alpha, we gave oral steroid in the condition that clinical symptoms were being improved gradually.

Specific Expression of Interferon-γ Induced by Synergistic Activation Mediator-Derived Systems Activates Innate Immunity and Inhibits Tumorigenesis

( Shuai Liu ),( Xiao Yu ),( Qiankun Wang ),( Zhepeng Liu ),( Qiaoqiao Xiao ),( Panpan Hou ),( Ying Hu ),( Wei Hou ),( Zhanqiu Yang ),( Deyin Guo ),( Shuliang Chen ) 한국미생물생명공학회 2017 Journal of Microbiology and Biotechnology Vol.27 No.10

The synergistic activation mediator (SAM) system can robustly activate endogenous gene expression by a single-guide RNA. This transcriptional modulation has been shown to enhance gene promoter activity and leads to epigenetic changes. Human interferon-γ is a common natural glycoprotein involved in antiviral effects and inhibition of cancer cell growth. Large quantities of high-purity interferon-γ are important for medical research and clinical therapy. To investigate the possibility of employing the SAM system to enhance endogenous human interferon-γ with normal function in innate immunity, we designed 10 single-guide RNAs that target 200 bp upstream of the transcription start sites of the interferon-γ genome, which could significantly activate the interferon-γ promoter reporter. We confirmed that the system can effectively and highly activate interferon-γ expression in several humanized cell lines. Moreover, we found that the interferon-γ induced by the SAM system could inhibit tumorigenesis. Taken together, our results reveal that the SAM system can modulate epigenetic traits of non-immune cells through activating interferon-γ expression and triggering JAK-STAT signaling pathways. Thus, this strategy could offer a novel approach to inhibit tumorigenesis without using exogenous interferon-γ.

LPS로 자극한 Raw 264.7 cell에서 황금(黃芩)의 type 1 interferon 억제 효과

국윤범,Kook, Yoon-Bum 대한한의학방제학회 2008 대한한의학 방제학회지 Vol.16 No.2

Objective : The present study was designed to investigate whether the water extract of the root of Scutellaria baicalensis could regulate lipopolysaccharide (LPS)-induced type 1 interferon. Methods : To evaluate of type 1 interferon inhibitory effect of the root of Scutellaria baicalensis, we examined type 1 interferon in LPS-stimulated RAW264.7 cells. Furthermore, Interleukin (IL)-10 and interferon regulatory factor (IRF) - 1, 7 expression level were examined to study the inhibition mechanisms. Results 1. Extract from the root of Scutellaria baicalensis didn't have any cytotoxity itelf. 2. Extract from the root of Scutellaria baicalensis inhibited interferon-a,b in dose dependant- and type 1 interferon production in time dependant manner. 3. Extract from the root of Scutellaria baicalensis reduced IL-10 and IRF-1, 7 production in LPS-stimulated RAW 264.7 cells. Conclusion : The extract from the root of Scutellaria baicalensis down-regulated LPS-induced type 1 interferon through suppression of IL-10 and IRF-1, 7 expression. This results suggested that the extract from the root of Scutellaria baicalensis may be a beneficial drug against inflammatory diseases.

수두 - 대상포진 바이러스 감염환자의 혈청내 Interferon의 정량에 관한 연구

한을남(Eul Nam Han),임수덕(Soo Duck Lim) 대한피부과학회 1985 대한피부과학회지 Vol.23 No.2

Recently, the importance of interferons as immune modulators has been recognized. Measurement of serum or tissue levels give only a partial picture of interferon activity, since antiviral effects persist after levels become undetectable. Neverthless, serum levels correlate reasonably well with clinical effects. Authors have analyzed the serum interferon levels in 12 patients with varicelIa and 25 with herpes zoster and the results are compared with healthy normal control. The results are as follows. The mean value of serum interferon levels showed no significant difference between patients group with varicella and with herpes zoster (8. 4+8, 5units/ml) and normal healthy control group (6. 2+7. 2 units/ml), 2, The mean value of serum interferon levels showed no significant difference between patients group with varicella (9. 2+7. 8 unit/ml) and normal healthy control group. 3 The mean value of serum interferon levels showed no significant difference between patients group with herpes zoster (8. I+9. 0 units/ml) and normal healthy control group. 4 The mean value of serum interferon levels showed no significant difference between patients group of varicella and those of herpes zoster.

인터페론을 사용한 만성 B 형 간염환자에서 인터페론 중화항체의 발현

지종대(Jong Dae Ji),이신형(Sin Hyeung Lee),김연수(Yun Soo Kim),서동진(Dong Jin Suh) 대한내과학회 1994 대한내과학회지 Vol.46 No.2

Background: It has been suggested that the deveolpment of neutralizing antibody to interferon (anti-IFN) in patients treated with recombinant IFN-α may decrease the therapeutic effect of interferon. We studied the incidence of development and the clinical significance of interferon neutralizing antibody in patients with chronic HBV infection treated with recombinant interferon α-2b (intron A). Methods: 32 patients with chronic HBV infection, who had been positive for HBeAg and HBV DNA for more than twelve months were studied. Serum samples were collected before IFN trial, within 1~2 months after administration and 1 month after cessation of therapy. When duration of treatment were long, serum samples were collected repeatedly within 4~5 months after administation. Sera were stored at -20℃ and subsequently tested for anti-IFN. Test for anti-IFN were performed by an assay which measures the neutralization of the antiviral activity of interferon alfa-2b in a system using EMC virus and FS-4 cells (strain of dipoloid fibroblsasts derived from a neonatal foreskin). Results: 1) 1nterferon neutralizing antibody developed in 6(18.6%) of 32 patients treated with interfern α-2b and titers of anti-IFN were low at 10~20. 2) No correlation was seen between sex, age, or pretreatment serum ALT level and the development of anti-IFN. But anti-INF was significantly more likely to develop in patients who received lower dose (3 MU) of IFN than in those patients received higher doses (5 MU or 6 MU): 36% VS 5% (p=0.04). 3) HBV DNA became negative in 5(19%) patients without anti-IFN and in 1(17%) patients with anti-IFN (p=0.46, not significant). 4) HBeAg was seroconverted in 8(31%) patients with- out anti-IFN and in 1(17%) patients with anti-IFN (p= 0.41, not significant). Conclusion: It is suggested that interferon neutralizing antibody would not influence the therapeutic effect of interferon in chronic HBC infection.

인터페론 단독 투여에 지속적 치료 효과가 없었던 만성 C 형 간염 환자에서의 인터페론과 리바비린의 병용 치료

이천균 ( Chun Kyun Lee ),한광협 ( Kwang Hyub Han ),정정일 ( Jeong Il Jeong ),최원 ( Won Choi ),최병현 ( Byung Hyun Choe ),김부일 ( Vu Il Kim ),이관식 ( Kwan Sik Lee ),전재윤 ( Chae Yoon Chon ),문영명 ( Young Myoung Moon ),김영아 대한소화기학회 1999 대한소화기학회지 Vol.33 No.2

Background/Aims: Interferon-alpha has been effective in 10-20% of treated patients with chronic hepatitis C (CH-C) on a long term basis. We conducted this study to evaluate the biochemical and virological outcomes of combined treatment with interferon alpha and ribavirin for the patients who had CH-C but showed non-response or relapse to interferon alpha alone. Methods: Twenty five patients with CH-C who had not responded or relapsed to interferon alpha alone treatment were enrolled. Eighteen patients were given by the combined treatment of interferon alpha and ribavirin and 7 patients were not given any specific treatment as control. Interferon alpha-2a was given subcutaneously, at a dose of 4.5 MU thrice weekly. Ribavirin was also given orally, at a dose of 900 mg/day for 24 weeks. We quantified serum HCV-RNA levels at the end of treatment. Results: The normalization rate of serum ALT at the end of treatment was 47.1% (8/17) in treated group and 14.3% (1/7) in control group and negative conversion of HCV-RNA was noted in all patients. In the treated group, 75% (6/8) of responders at the end of treatment sustained serum ALT level normally during 24 weeks follow-up, but none has responded persistently in the control group. Conclusions The combined treatment with interferon alpha and ribavirin is effective and safe for treating chronic hepatitis C in patients who showed non-response or relapse to interferon alone. (Kor J Gastroenterol 1999;33:232 - 239)