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 大韓韓方內科學會誌 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.

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

N/A 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.

소아의 B형 만성 활동성 간염에서 저용량 ${\alpha}$-Interferon과 Thymodulin의 병용 치료 효과

최병호,고철우,Choe, Byung-Ho,Ko, Cheol-Woo 대한소아소화기영양학회 1998 Pediatric gastroenterology, hepatology & nutrition Vol.1 No.1

목 적: 만성 B형 간염 환자의 치료에 많은 항바이러스제와 면역조절 물질이 시도되었지만 현재까지는 ${\alpha}$-interferon만이 일정한 효과가 있는 것으로 보고되고 있다. 또 면역조절제 중에는 현재thymodulin 등의 면역증강 물질이 시도되어지고 있다. 저자들은 interferon 치료시 thymodulin을 병용하면 소아의 B형 만성 활동성 간염에 interferon 단독 치료보다 효과가 있는지를 조사해 보았다. 대상 및 방법: 1990년 3월부터 1996년 2월까지 경북대학교병원 소아과에 입원하였던 환아 중 6개월 이상 HBsAg과 HBeAg 및 HBV DNA가 양성(1+~4+)이고, 혈청 AST와 ALT치가 상승되어 있으며 간조직 검사상 만성 활동성 간염으로 확진된 환아 23명($9.8{\pm}2.8$세)을 대상으로 recombinant ${\alpha}$-interferon 300 MU($280\;MU/m^2{\pm}68$; 범위: $189{\sim}448\;MU/m^2$)를 주 3회씩 6개월간 피하 주사하였다. 그 중 10명에게는 thymodulin 60 mg을 매일 복용시켰고 13명은 ${\alpha}$-interferon만 투여하였으며 치료 종료 후 최소 12개월 이상 추적 검사를 하였다. 양군간의 모든 변수에서 통계학적 유의차는 없었다. 결 과: 1) 23명 전예에서 interferon 치료 중에 AST, ALT 및 HBV DNA의 감소가 있었고 12개월째 추적 검사상 9명(39%)에서 평균 3.1개월째에 HBeAg과 anti-HBe의 혈청전환 및 HBV DNA의 음전이 생겼으며 18개월째 추적검사에서는 이 중 2명에서 ${\alpha}$-interferon 중단 후 8개월과 9개월에 HBeAg이 다시 나타났고 또 다른 2명에서 추가로 혈청전환이 생겨서 전체적으로는 23명의 환아 중 11명(48%)에서 혈청전환이 생겼고 재발한 2명을 빼면 최종 성적은 9명(39%)이 된다. 2) 수직 감염이 있는 7례 중 2례(29%)에서 혈청 전환이 생긴 반면 수직 감염이 없는 12례 중 6례(50%)에서 혈청전환이 생겨 수직 감염 유무는 혈청전환과의 상관 관계가 밀접하다고 생각한다. 3) ${\alpha}$-interferon 치료 전의 ALT치가 정상치의 2배 이하인 경우 8례 중 3례(38%)에서 혈청전환이 있었는데 비해 2배 이상이었던 경우는 15예 중 8례(53%)에서 혈청전환이 있어서 ${\alpha}$-interferon 치료전의 높은 ALT치가 좋은 치료 효과를 예측하는데 도움이 될 수 있을 것으로 생각한다. 4) ${\alpha}$-interferon 치료 전의 HBV DNA가 3+ 이상이었던 경우는 12례 중 5례(42%)에서 혈청전환이 있었는데 비해 1+ 이었던 경우는 11례 중 6례(55%)에서 혈청전환이 있어서 ${\alpha}$-interferon 치료전의 낮은 HBV DNA가 좋은 치료 효과를 예측하는데 도움이 될 수 있을 것으로 생각한다. 5) B형 만성 활동성 간염 환아 23례 중 10례에게 thymodulin을 병용하여 투여하였으나 10례 중 5례(50%)에서 혈청전환이 있었으며 이는 대조군인 ${\alpha}$-interferon 단독 치료 시의 13례 중 6례(46%)와 비교할 때 통계적인 의의를 찾을 수 없었다. 결 론: 면역조절 물질인 thymodulin의 투여로써 숙주 면역계의 기능을 증강시켜 바이러스의 제거를 촉진하고자 소아의 B형 만성 활동성 간염에 ${\alpha}$-interferon 치료시 thymodulin을 병용하여 치료하였으나 ${\alpha}$-interferon 단독 치료보다 더 효과가 있다고 볼 수는 없었으며 향후 더 많은 환아를 대상으로 한 interferon과 다른 종류의 항바이러스제 및 면역조절제 등과의 병용 치료 연구가 더 좋은 결과를 얻기 위해 필요할 것으로 생각한다. Purpose: Though many antiviral or immunomodulatory agents have been used in patients with chronic HBV hepatitis, interferon is considered to be the only effective therapeutic agent so far. Among immunomodulatory agents, thymodulin, the oral form of thymosin, is currently in clinical trial. We compared the efficacy of alfa-interferon therapy alone with a combined therapy of alfa-interferon and thymodulin in children with chronic active hepatitis B. Method: Twenty three children aged 4.4~13.7 years who were known to be positive for HBsAg and HBeAg in serum for at least 6 months and who had biopsy-proven chronic active hepatitis were given either combined therapy of alfa-interferon and thymodulin or alfa-interferon alone, and all children were HBV DNA positive in their serum at the beginning. Follow-ups have been done for at least 1 year after a 6 month course of therapy and clearance of viral replication markers has been evaluated. Results: 1) During follow up period, 11 (48%) children were seroconverted to anti-HBe and were cleared of HBV DNA from their serum. However, 2 of them relapsed after discontinuance of interferon therapy. 2) Seroconversion occurred more frequently among those who had not been vertically transmitted, had elevated serum ALT levels and low HBV DNA levels before interferon therapy. 3) There was no significant advantage of the combined therapy with thymodulin compared to interferon therapy alone. Conclusion: Combined therapy of alfa-interferon and thymodulin failed to demonstrate synergistic effect. We think that combination therapies of alfa-interferon with other antiviral or immunomodulatory agents need to be studied in order to achieve better therapeutic responses.

소아 만성 B형 간염 환아에서 Interferon-${\alpha}$의 용량 차이 및 재치료에 따른 치료 효과 비교

장창환,이경희,황위경,오기원,박우생,이준화,고철우,최병호,Jang, Chang-Hwan,Lee, Kyung-Hee,Hwang, Wi-Kyung,Oh, Ki-Won,Park, Woo-Saeng,Lee, Jun-Hwa,Ko, Cheol-Woo,Choe, Byung-Ho 대한소아소화기영양학회 2003 Pediatric gastroenterology, hepatology & nutrition Vol.6 No.2

목 적: 소아의 만성 B형 간염 치료에 interferon-${\alpha}$의 일정한 치료 효과가 보고되고 있다. 저자들은 interferon-${\alpha}$의 용량 차이에 따른 치료 효과 및 초치료와 재치료에 따른 치료 효과에 차이가 있는지 비교해 보았다. 방 법: 1990년 3월부터 1999년 8월까지 경북대학교병원 소아과에 내원하였던 환아(2~14세) 중 6개월 이상 HBsAg, HBeAg 및 HBV DNA가 양성이고, 혈청 ALT치가 상승되어 있는 51명의 환아를 대상으로 27명에게 interferon-${\alpha}$ $3MU/m^2$ ($2.66{\pm}0.66\;MU/m^2$)를 투여하였고 24명에게는 $6\;MU/m^2$ ($4.45{\pm}0.94\;MU/m^2$)을 주 3회씩 6개월(6~12개월)간 피하 혹은 근육 주사하였다. interferon-${\alpha}$ 초치료 평균용량은 $3.50{\pm}1.20\;MU/m^2$이었고 평균 치료 기간은 7개월(6~12개월)이었다. 초치료에 반응이 없었던 환아 중 12명을 대상으로 다시 interferon-${\alpha}$ 재치료를 시행하였다. 재치료 평균 용량은 $3.62{\pm}1.51\;MU/m^2$이었고 평균 치료 기간은 7개월(6~12개월)이었다. 용량 차이를 보인 두 군 사이에 성별, 연령, 치료기간, 치료전 ALT치와 HBV DNA 등에서는 통계학적으로 유의한 차이가 없었으며 초치료, 재치료 두 군간에도 유의한 차이가 없었다. 결 과: 치료 시작 1년 후 시점에서 interferon $3\;MU/m^2$로 치료한 27명 중 11명(41%)에서 ALT의 정상화를 보였고 9명(33%)에서 HBeAg이 anti-HBe로 혈청전환이 되었다. 한편 $6\;MU/m^2$ 치료군 24명 중 에서는 12명(50%)에서 ALT의 정상화를 보였고 7명(29%)에서 혈청전환이 되었는데 두 군 사이의 치료성적에는 통계학적으로 유의한 차이가 없었다. Interferon $3\;MU/m^2$ 치료군에서 발생한 부작용으로는 발열 14례(52%), 백혈구 감소증 10례(37%)였으며 모든 경우에서 특별한 조치 없이 회복되었다. 한편 interferon $6\;MU/m^2$ 치료군에서는 발열 16례(67%), 백혈구 감소증 8례(33%), 혈소판 감소증 1례(4%), 갑상선 기능 저하증 2례(8%)가 있었다. 치료와 관련된 부작용도 두 군 간에 통계학적으로 유의한 차이가 없었다. Interferon-${\alpha}$ 초치료군 51명 중 23명(45%)에서 ALT의 정상화를 보였고 16명(31%)에서 혈청전환이 있었으며 재치료군은 12명 중 3명(25%)에서 ALT의 정상화 및 혈청전환이 있었다. 결 론: Interferon-${\alpha}$ $3\;MU/m^2$ 치료군과 $6\;MU/m^2$치료군을 비교했을 때 ALT의 정상화 및 혈청전환에서 의미 있는 치료 효과의 차이를 찾을 수 없었다. interferon-${\alpha}$ 재치료는 초치료만큼의 효과가 있음을 보여주었다. Purpose: We compared the therapeutic efficacy of low dose with that of standard dose of interferon (IFN) treatment and also compared the first IFN treatment with retreatment. Methods: We have studied 51 children (age, 2~14) treated for chronic hepatitis B from March 1990 to August 1999. Twenty seven children had been treated with $3\;MU/m^2$ ($2.66{\pm}0.66\;MU/m^2$) of IFN-${\alpha}$ three times a week for 6 months (range, 6~12 months), whereas 24 children with $6\;MU/m^2$ ($4.45{\pm}0.94\;MU/m^2$). There was no significant difference in gender, age, initial ALT and HBV DNA levels between each comparative group. Results: Among the 27 children treated with $3\;MU/m^2$ of IFN, ALT level had normalized in 11 children (41%) and anti-HBe seroconversion occurred in 9 children (33%) one year after the initiation of treatment. In comparison, among the 24 children treated with $6\;MU/m^2$ of IFN, ALT normalized in 12 children (50%) and anti-HBe seroconversion occurred in 7 children (29%). In comparing the first treatment group to retreatment group, ALT level had normalized in 23 children (45%) and anti-HBe seroconversion occurred in 16 children (31%) among the 51 children treated with the first course of IFN treatment. In comparison, ALT normalized and anti-HBe seroconversion occurred in 3 children (25%) among the retreated 12 children. Conclusion: There was no significant difference in the therapeutic efficacies between $3\;MU/m^2$ and $6\;MU/m^2$ dose of IFN treated groups in ALT normalization and anti-HBe seroconversion. The retreatment efficacy of IFN-${\alpha}$ was as effective as the first treatment.

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

목 적: 인터페론은 소아 만성 B형 간염의 치료에 널리 쓰이고 있으나 50% 이상의 환자에서 인터페론 치료에 반응이 없어 추가적인 다른 치료가 필요하다. 라미부딘은 B형 간염 바이러스 복제의 억제제로 B형 간염 치료제로 널리 쓰이고 있으나, 인터페론 치료에 반응이 없었던 B형 간염 환자에 대한 라미부딘의 치료 효과에 대한 연구가 많지 않다. 방 법: 2000년 1월부터 2007년 12월까지 부산대학교병원 소아청소년과에서 만성 B형 간염으로 진단되어 인터페론(interferon ${\alpha}$-2b, 10 $MU/m^2$ 또는 pegylated interferon $1.5{\mu}g/kg$)으로 6개월 간 치료를 받은 33명 중 치료에 반응이 없어 치료 종결 후 6~12개월 뒤부터 라미부딘(3 mg/kg/일, 최고 100 mg/일)으로 치료를 한 8명(남 6명, 여 2명)을 대상으로 라미부딘의 치료 효과를 분석하였다. 임상적 소견에 대해 의무기록지를 후향적으로 검토하였다. 결 과: 인터페론 치료 시작 시 나이는 4.9${\pm}$3.1세, 라미부딘 치료 시작 시 나이는 6.1${\pm}$3.2세였다. 인터페론 치료 전 혈청 ALT는 148.1${\pm}$105.8 IU/L였고, HBV-DNA PCR log값은 6.95${\pm}$0.70 copies/mL였다. 인터페론 치료 후 ALT는 143.1${\pm}$90.4 IU/L였고, DNA PCR log값은 6.46${\pm}$2.08 copies/mL로 치료 전과 차이가 없었고(p> 0.05), 2명에서 HBeAg 음전이 있었다. 모든 환자에서 라미부딘 치료 후 7.4${\pm}$2.1개월에 ALT가 정상화되고, 이미 HBeAg이 음전된 2명을 제외한 6명에서 7.9${\pm}$2.1개월에 HBeAg 혈청전환이 있었다. HBV DNA는 2.4${\pm}$2.8개월에 7명(87.5%)에서 음성화되었다. 2명은 라미부딘치료 종결 후 3년 이상 재발이 없으며, 5명은 완전 반응상태로 24.4${\pm}$9.1개월간 복용 중이다. 1명은 12개월간 라미부딘을 복용하여 혈청 ALT가 정상화되고 HBeAg 혈청전환이 있었으나 바이러스 돌파현상이 발생하여 치료를 중단하였다. 결 론: 연구 대상 환자 수가 적었지만 인터페론 치료에 반응이 없었던 만성 B형 간염 환자에서 라미부딘의 치료는 매우 효과적이었다. 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.

소아 만성 B형 간염의 Interferon Alfa 치료 후 혈청학적, 조직학적 소견의 변화

고재성,정주영,장자준,서정기,Ko, Jae-Sung,Chung, Ju-Young,Jang, Ja-Joon,Seo, Jeong-Kee 대한소아소화기영양학회 2000 Pediatric gastroenterology, hepatology & nutrition Vol.3 No.1

목 적: 만성 B형 간염 환자의 치료에 interferon alfa는 효과가 있는 것으로 알려지고 있지만 연구자에 따라 차이가 있으며 소아에서의 치료 후의 조직학적 변화에 대한 연구는 거의 없는 실정이다. 저자들은 소아 만성 B형 간염에서 interferon alfa의 치료 효과와 추적 생검이 가능했던 환자에서의 조직학적 변화에 대해 알아보고자 하였다. 대상 및 방법: 1995년 3월부터 1997년 8월까지 서울대학교병원 소아과에서 6개월 이상 HBsAg과 HBeAg 및 HBV DNA가 양성이었으며 간 조직검사상 만성 간염으로 확진된 환자 35명을 대상으로 recombinant interferon alfa 3~6 MU(평균 $3.4\;MU/m^2$)를 주 3회씩 6개월간 피하주사 하였다. 치료 시작 12개월 이상 혈청학적 변화를 추적 관찰하였다. interferon에 반응이 있는 환자 중 18명에서 치료후 간생검을 실시하여 조직학적 변화를 분석하였다. 결 과: 1) 치료 환자 35명 중 17명(49%)에서 인터페론 치료 시작 6개월에 HBV DNA의 감소가 있었고, 12개월째에 22명(63%)에서 HBeAg 및 HBV DNA의 음전이 생겼으며 18개월까지는 25명(71%)에서 관찰되었다. 반응군에서 혈청 ALT치는 모두 정상화되었고, HBsAg의 음전은 1명에서 관찰되었다. 2) 어머니가 HBsAg 보유자가 아닌 수평감염, 치료전 ALT가 정상의 2배 이상, 간조직의 심한 괴사와 염증이 interferon에 대한 반응이 좋은 예측인자이었다. 3) 치료 후 반응군의 간조직 소견에서 간맥주위괴사, 소엽내 활성도, 간맥내 염증, 간섬유화, total HAI가 유의하게 감소하였다. 결 론: 소아 만성 B형 간염에서 interferon alfa 치료 후 63%에서 반응을 보였으며, 혈청학적 변화는 조직학적 소견의 호전과 연관이 있다. 소아 만성B형 간염 환아에서 interferon 치료는 혈청학적, 생화학적, 조직학적 관해를 유도하는 효과적이고 안전한 치료방법이다. Purpose: The aim of this study was to evaluate the efficacy and histologic changes of interferon-alfa therapy on chronic hepatitis B virus infection in children. Patients and Methods: Thirty five children aged 3~16 years who were seropositive for HBV DNA, HBsAg and HBeAg were enrolled. Interferon-alfa 2a ($3.4\;MU/m^2$) were given for 6 months. Serologic markers of viral replication was evaluated 1 year after therapy. Post treatment liver biopsy was performed in 18 patients who showed serologic response. Results: Serum HBeAg and viral DNA became negative in 22 (63%) of treated children at 12 months after therapy. Serum aminotransferase levels normalized in all of the responders and HBsAg became negative in one responder. Horizontal transmission, serum aminotransferase levels more than twice normal, and active inflammation on liver biopsy were predictive factors for response to interferon therapy. Periportal piecemeal necrosis, lobular activity, portal inflammation, fibrosis, and total histologic activity index were reduced in responders. Conclusion: In children with chronic hepatitis B, interferon alfa promotes loss of viral replication and improves aminotransferase. Serologic response is associated with improvement in hepatic histology.

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.

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(구 한국산업미생물학회) 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.

HBeAg 양성 만성 활동성 간염의 치료에 있어 α2b-Interferon의 효과 및 안정성에 관한 연구

신동현 ( Sin Dong Hyeon ),김신묵 ( Kim Sin Mug ),한상우 ( Han Sang U ),김세종 ( Kim Se Jong ) 대한내과학회 1993 대한내과학회지 Vol.44 No.1

연구배경 : B형 만성 활동성간염에서 B형 간염바이러스와 지속적인 증식은 만성 활동성간염의 간경변증과 원발성 간암으로 천이하는데 중요한 요인으로 알려져 B형 만성 활동성간염의 치료에 B형 간염바이러스의 증식을 억제할려고 하는 노력들이 진행되었었다. 그러나 최근에는 면역기능조절 장애가 만성 활동성 간염의 발생에 중요한 요인임을 감안하여 면역조절기능과 항바이러스 작용을 동시에 갖고 있는 interferon으로 만성 활동성간염을 치료해 보려는 연구들이 시도되고 있다. 방법 : 저자는 HBeAg 양성인 만성 활동성간염 환자 28예를 대상으로 합성 interferon 인 Intron-A^(R)을 1회에 300만 단위로 1주에 3회씩 12주간 피하주사하고 B형 간염 바이러스 증식의 표지자인 HBV DNA 및 HBeAg의 음전율과 간기능의 변화, 말초 혈액소견의 변화, BUN, 혈청 Creatinine, 요검사소견의 변화 및 부작용들을 2년간 추적 관찰하였기에 그 결과를 보고하는 바이다. 결과 : 1) 6주이상 지속적으로 음전된 HBeAg음전율은 HBeAg양성인 27예중 10예로 37% 이었다. 2) 6주이상 지속적으로 음전된 HBV DNA 음전율은 HBV DNA 양성인 187예중 16예로 88% 보였다. 3) 혈청 AST 및 ALT치는 투여 2주째부터 감소하기 시작하여 2년까지 투여 시작전에 비해 유의하게 감소된 상태를 유지하고 있었다(p<0.05). 4) 말초 혈액소견은 투여 2주째부터 백혈구, 과립백혈구 및 혈소판수의 감소가 관찰되었으나 6주내지 8주부터 증가하기 시작하여 24주경부터는 투약전의 상태로 정상화 되었다. 5) BUN, 혈청 creatinine 및 요검사 소견은 2년간 추적관찰에서 이상없이 모두 정상이었다. 6) a_2b-interferon 투여로 인한 부작용은 발열(89%), 근육통(89%), 피로감(67%), 두통(57%), 식욕부진(50%), 오심(35%), 주사부위 피부발진(25%), 설사(17%), 탈모증(7%), 불면증(3%), 극심한 전신 근무력중(3%)등의 순이었으나 전례에서 경미한 정도였고 6주째 극심한 근무력증을 호소한 1예에서는 투여를 중단하였다. 결론 : B형 만성 활동성 간염 환자에서 300만 단위 IFN를 주3회, 12주간 피하투여하는 방법은 HBV DNA와 HBeAg을 소실시키며 aminotransferase를 감소 또는 정상화 시키고, 조혈기관이나 신기능에 장애를 일으키지 않고, 심한 임상적 부작용을 나타내지는 않는 비교적 안전한 치료방법으로 생각되었다. Background : It was Known that the persistent replication of hepatitis B virus in chronic active hepatitis was an important cause of developing liver cirrhosis and hepatocellular carcinoma and several antiviral agents was tried in protecting viral replication. But recently, interferon functioning as an immune modulator and antiviral agents has been tried in treating chronic active hepatitis B. Methods : The efficacy and safety of recombinant interferon a_2b (Intron-A^(R) was studied in twenty eitght cases with HBeAg positive chronic active hepatitis (CAH). Three million units of interferon were administrated subcutaneously three times a week for 12 weeks. The negativity of HBV DNA and HBeAg,m activities of aminotransferase, BUN, serum creatinine and urinalysis were followed up for 2 years in 28 cases with HBeAg positive CAH. The peripheral blood white blood cell, granulocyte and platelet count were followed-up for 2 years. The negativity of HBV DNA and HBeAg was regarded as persistent negativity more than 6 weeks in follow up period. Results : the result were as follows 10 HBeAg negativity more than 6 weeks for 2 years were observed in 10 cases (37%) out of 27 cases. 2) HBV DNA negativity more than 6 weeks for 2 years were observed in 16 cases(88%) out of 18 cases with HBV DNA positive cases. 3) During administration of interferon, serum aspartate aminotransferas (AST) and allanin aminotransferase (ALT0 were decreased significantly from the 2nd week after th initial injection to the 116th week (p<0.05). 4) The peripheral white blood cell, granulocyte and platelet counts were decreased from the 2nd week but recovered from the 6th to the 8th week in 28 cases. These were within normal limits within 24 weeks. 5) There were no specific changes in BUN, serum creatinine and urinalysis by a_2b-interferon administration. 6) Fever(89%), myalgia(89%), fatigue(67%), headache(57%), anorexia(50%), nausea(35%), skin eruption at injected site (21%), diarrhea(17%), alopecia(7%), insomnia(3%) and severe generalized muscle weakness (3%) were noted in the first few weeks as adverse effects. But these were mild in all cases and subsided within first few weeks. We stopped the injection in a case with uncontrollable severe generalized muscle weakness at the 6th week. Conclusion : In chronic active hepatitis B, a subcutaneous administration of three million units of interferon at interval of theree times a week for 12 weeks can be used safely without a significantly adverse effects. Also it may cause a loss of HBV DNA and HBeAg and reduce or normalize the titers of aminotransferase.

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.