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.

[P470] Cutaneous vasculitis associated with interferon beta-1b treatment for multiple sclerosis

( Su Hyun Park ),( Myeong Heon Chae ),( Ji Yeoun Lee ),( Tae Young Yoon ) 대한피부과학회 2017 대한피부과학회 학술발표대회집 Vol.69 No.1

Interferon beta-1b is a cytokine in the interferon family used to treat multiple sclerosis. Therapy with interferon beta-1b may be associated with a number of adverse reactions. Relatively frequent side effects include flu-like symptoms, transient laboratory abnormalities, menstrual disorders, and increased spasticity. It can also cause skin reactions include cutaneous necrosis at the injection site. However, a case of cutaneous vasculitis associated with interferon beta-1b treatment has never been reported in the Korean literature. A 24-year-old woman with multiple sclerosis presented with erythematous skin lesions on her trunk and both upper and lower extremities for 4 days. 10 months ago, she started interferon beta-1b treatment for multiple sclerosis. 6 days ago, she injected interferon beta-1b subcutaneously on her abdomen. 4 days ago, erythematous papuloplaques were developed at the injection site, and then spreaded on the trunk and both upper and lower extremities with symmetric distribution. Histologic findings showed the presence of vascular and perivascular infiltration of polymorphonuclear leukocytes with formation of nuclear dust, extravasation of erythrocytes, and fibrinoid necrosis of the vessel walls. Based on these findings, a diagnosis of leukocytoclastic vasculitis was made. Herein, we report a case of cutaneous vasculitis associated with interferon beta-1b treatment for multiple sclerosis.

인터페론 베타로 치료한 소아의 재발-이장 다발성 경화증 1례

조명현(Myung Hyun Cho),송민경(Min Kyoung Song)곽병옥(Byung Ok Kwak),이란(Ran Lee) 대한소아신경학회 2015 대한소아신경학회지 Vol.23 No.3

다발성 경화증은 젊은 성인에 주로 발생하는 면역 매개성 탈수초 중추신경계 질환으로 10세 이하에서 발병하는 경우는 드물다. 본 증례는 34개월 남아로 H1N1 독감 예방 접종하고 일주일 후 발생한 발작, 좌측 상하지의 근력 저하, 좌측 상지의 의도 진전을 주소로 내원 하였다. 뇌 자기공명영상 T2 강조영상에서 좌측 시상, 양측 중간뇌, 교뇌, 숨뇌, 대뇌겉질, 피질하 백질에서 고신호강도를 보였다. 처음에는 급성파종뇌척수염으로 생각하여 메틸프레드니솔론을 투여하여 호전 되었으나 15개월 후 보행 장애, 의도 진전, 구어장애를 보여서 다시 시행한 뇌 자기공명영상 T2 강조영상에서 새로운 병변이 보였다. 이에 다발성 경화증으로 진단하고 인터페론 베타를 격일로 투여하여 증상이 호전되었다. 인터페론 베타 치료 중 감기 같은 증상 보여서 중단하자 곧바로 다발성 경화증이 재발하였다. 메틸프레드니솔론으로 치료 하였고 현재 인터페론 베타를 투여 받으며 재발 없이 지내고 있다. 본 증례를 통하여 인터페론 베타는 소아 다발성 경화증의 재발을 억제 하며, 인터페론 베타를 짧은 기간이라도 중단할 경우 다발성 경화증 이 재발할 수 있음을 경험하였다. Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central ner-vous system that is primarily a disease of young adulthood. Onset before 10 years of age is considered unusual. We report a boy with MS with onset at 34 months of age who was effectively treated with interferon beta 1b. He visited the emergency room with seizure, left-side limb weakness, and intentional tremor on the left hand. He had received influenza (H1N1) vaccination 1 week prior to that event. Brain mag-netic resonance imaging (MRI) disclosed multifocal edematous T2-weighted hyper-intensity lesions in the left thalamus, bilateral midbrain, pons, medulla, cerebral cortices, and subcortical white matter. This presentation suggested the diagnosis of ADEM. Intravenous methylprednisolone was administered and the symptoms rec overed completely. Fifteen months later, he experienced gait disturbance, inten-tional tremor, and dysarthria and a new T2-weighted hyperintensity lesion was found on brain MRI. The diagnosis of early-onset MS was made and the patient was administered interferon beta-1b every other day. He was relapse free after the treat ment. However, he experienced flu-like symptoms and intermittent fever and temporary withdrawal of interferon beta-1b led to relapse of MS. Intravenous me-thylprednisolone was administered again and his symptoms improved gradually. Currently, at 5 years of age, he has been relapse free from 3 months after interferon beta-1b was administered consistently. This case showed that interferon beta had positive effects to reduce relapses in pediatric MS patients, and pediatric MS relapsed during withdrawal of interferon beta for a short period.

Interferon-gamma, Tumor Necrosis Factor-alpha및 Transforming Growth Factor-beta(1)에 의한 골수세포의 유착분자 발현 및 Stromal Cell-Derived Factor-1 생성의 조절

조덕연,황진희,정효균,박수진,박상은,곽승근,윤환중,성주명,김삼용 大韓血液學會 2003 大韓血液學會誌 Vol.38 No.2

Induction of Apoptosis in Glioma Cells and Upregulation of Fas Expression Using the Human Interferon-β Gene

Guo, Yan,Wang, Gan,Gao, Wen-Wei,Cheng, Shi-Wen,Wang, Ren,Ju, Shi-Ming,Cao, He-Li,Tian, Heng-Li Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.6

We investigated whether IFN-${\beta}$ inhibits the growth of human malignant glioma and induces glioma cell apoptosis using the human IFN-${\beta}$ gene transfected into glioma cells. A eukaryonic expression vector ($pSV2IFN{\beta}$) for IFN-${\beta}$ was transfected into the glioma cell line SHG44 using liposome transfection. Stable transfection and IFN-${\beta}$ expression were confirmed using an enzyme-linked immunosorbent assay (ELISA). Cell apoptosis was also assessed by Hoechst staining and electron microscopy. In vivo experiments were used to establish a SHG44 glioma model in nude mice. Liposomes containing the human IFN-${\beta}$ gene were injected into the SHG44 glioma of nude mice to observe glioma growth and calculate tumor size. Fas expression was evaluated using immunohistochemistry. The IFN-${\beta}$ gene was successfully transfected and expressed in the SHG44 glioma cells in vitro. A significant difference in the number of apoptotic cells was observed between transfected and non-transfected cells. Glioma growth in nude mice was inhibited in vivo, with significant induction of apoptosis. Fas expression was also elevated. The IFN-${\beta}$ gene induces apoptosis in glioma cells, possibly through upregulation of Fas. The IFN-${\beta}$ gene modulation in the Fas pathway and apoptosis in glioma cells may be important for the treatment of gliomas.

$p21^{WAF1}$ Is Involved in Interferon-${\beta}$-Induced Attenuation of Telomerase Activity and Human Telomerase Reverse Transcriptase (hTERT) Expression in Ovarian Cancer

Lee, Ji-Hae,Lee, Seung-Yeul,Lee, Je-Ho,Lee, Seung-Hoon Korean Society for Molecular and Cellular Biology 2010 Molecules and cells Vol.30 No.4

Telomerase activation is a key step in the development of human cancers. Interferon-${\beta}$ (IFN-${\beta}$) signaling induces growth arrest in many tumors but the anticancer mechanism of IFN-${\beta}$ is poorly understood. In the present study, we show that IFN-${\beta}$ signaling represses telomerase activity and human telomerase reverse transcriptase (hTERT) transcription in ovarian cancer and suggest that this signaling is mediated by $p21^{WAF1}$. IFN-${\beta}$ triggered down-regulation of telomerase activity and hTERT mRNA expression and also induced p21 expression, independently of p53 induction. Ectopic expression of p21 attenuated hTERT promoter activity. Murine embryonic fibroblasts (MEFs) genetically deficient in p21 (p21-/-) showed elevated (> 15 times) hTERT promoter activity compared to wild-type MEFs. Overexpression of p21 reduced the hTERT promoter activity of p21-/- MEFs and hTERT mRNA expression in HCT116 $p21^{WAF1}$ cell. These findings provide evidence that p21 is a potential mediator of IFN-${\beta}$-induced attenuation of telomerase activity and tumor suppression.

Inhibitory Effect of IFN-$\beta$, on the Antitumor Activity of Celecoxib in U87 Glioma Model

Kim, Eun-Kyoung,Chung, Dong-Sup,Shin, Hye-Jin,Hong, Yong-Kil The Korean Neurosurgical Society 2009 Journal of Korean neurosurgical society Vol.46 No.6

Objective : Interferon-$\beta$, (IFN-$\beta$) has been used in the treatment of cancers. Inhibition of the enzyme cyclooxygenase (COX) with celecoxib had a significantly suppressive effect on tumor growth, angiogenesis, and metastasis in a variety of tumors. The aim of this study was to elucidate the antiglioma effect of combined treatment with IFN-$\beta$ and celecoxib in U87 glioma model. Methods : The in vitro effects of IFN-$\beta$ (50-1,000 IU/mL) and celecoxib ($50-250\;{\mu}M$) alone or combination of both on the proliferation and apoptosis of U87 cells were tested using MTT assay, FACS analysis and DNA condensation. To determine the in vivo effect, nude mice bearing intracerebral U87 xenograft inoculation were treated with IFN-$\beta$ intraperitoneally ($2{\times}10^5\;IU/day$ for 15 days), celecoxib orally (5, 10 mg/kg) or their combination. Results : IFN-$\beta$ or celecoxib showed an inhibitory effect on the proliferation of U87 cells. When U87 cells were treated with IFN-$\beta$ and celecoxib combination, it seemed that IFN-$\beta$ interrupted the antiproliferative and apoptotic activity of celecoxib. No additive effect was observed on the survival of the tumor bearing mice by the combination of IFN-$\beta$ and celecoxib. Conclusion : These results suggest that IFN-$\beta$ seems to inhibit the antiglioma effect of celecoxib, therefore combination of IFN-$\beta$ and celecoxib may be undesirable in the treatment of glioma.

다발성경화증 치료를 위한 인터페론 베타의 산업적 생산

손다진(Da-Jin Son),김종석(Jong-Seok Kim),박재범(Jae-Bum Park),권덕호(Deok-Ho Kwon),정형무(Hyung-Moo Jung),한상인(Sang-In Han),홍억기(Eock-Kee Hong),하석진(Suk-Jin Ha) 한국생물공학회 2018 KSBB Journal Vol.33 No.2

Multiple sclerosis is a chronic disorder commonly occurred in the central nervous system and is an autoimmune disease. Corticosteroids are used as a short-term treatment for multiple sclerosis, but they cause side effects. Therefore, interferon beta having antiviral and anti-inflammatory effects, is used for long-term treatment. Interferon beta-1a, produced in Chinese hamster ovary cells, is glycosylated upon biosynthesis and forms glycoform, which is similar to naturally occurring protein. However, its process has disadvantages such as slow cell growth, low yield and high contamination possibility. Also, recombinant Escherichia coli is widely used for the production of interferon beta-1b due to its rapid growth and easy process scale up, but it lacks post-translational modification, leading to low activity. In addition, the produced Interferon beta-1b might cause protein aggregation due to misfolding. Alternatively, yeast can be used as a production host possessing N-glycosylation activity. Therefore, the choice of expression system in the production of interferon beta should be carefully selected in relation to the quality and yield.

Combination Therapy for Gliomas Using Temozolomide and Interferon-Beta Secreting Human Bone Marrow Derived Mesenchymal Stem Cells

Park, Jae-Hyun,Ryu, Chung Heon,Kim, Mi Jin,Jeun, Sin-Soo The Korean Neurosurgical Society 2015 Journal of Korean neurosurgical society Vol.57 No.5

Objective : Malignant gliomas are the most common primary tumors of the central nervous system and the prognosis of patients with gliomas is poor. The combination of interferon-bata (IFN-${\beta}$) and temozolomide (TMZ) has shown significant additive antitumor effects in human glioma xenograft models. Considering that the poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor, the tropism of human bone marrow-derived mesenchymal stem cells (MSC) for malignant gliomas can be exploited to therapeutic advantages. We investigated the combination effects of TMZ and MSCs that secrete IFN-${\beta}$ on gliomas. Methods : We engineered human MSCs to secret mouse IFN-${\beta}$ (MSC-IFN-${\beta}$) via adenoviral transduction and confirmed their secretory capacity using enzyme-linked immunosorbent assays. In vitro and in vivo experiments were performed to determine the effects of the combined TMZ and MSC-IFN-${\beta}$ treatment. Results : In vitro, the combination of MSC-IFN-${\beta}$ and TMZ showed significantly enhanced antitumor effects in GL26 mouse glioma cells. In vivo, the combined MSC-IFN-${\beta}$ and TMZ therapy significantly reduced the tumor size and improved the survival rates compared to each treatment alone. Conclusion : These results suggest that MSCs can be used as an effective delivery vehicle so that the combination of MSC-IFN-${\beta}$ and TMZ could be considered as a new option for the treatment of malignant gliomas.

Suppression of the growth of human colorectal cancer cells by therapeutic stem cells expressing cytosine deaminase and interferon-β via their tumor-tropic effect in cellular and xenograft mouse models

Yi, B.R.,Park, M.A.,Lee, H.R.,Kang, N.H.,Choi, K.J.,Kim, S.U.,Choi, K.C. Elsevier BV 2013 MOLECULAR ONCOLOGY Vol.7 No.3

Genetically engineered stem cells (GESTECs) exhibit a potent therapeutic efficacy via their strong tumor tropism toward cancer cells. In this study, we introduced the human parental neural stem cells, HB1.F3, with the human interferon beta (IFN-β) gene which is a typical cytokine gene that has an antitumor effect and the cytosine deaminase (CD) gene from Escherichia coli (E. coli) that could convert the non-toxic prodrug, 5-fluorocytosine (5-FC), to a toxic metabolite, 5-fluorouracil (5-FU). Two types of stem cells expressing the CD gene (HB1.F3.CD cells) and both the CD and human IFN-β genes (HB1.F3.CD.IFN-β) were generated. The present study was performed to examine the migratory and therapeutic effects of these GESTECs against the colorectal cancer cell line, HT-29. When co-cultured with colorectal cancer cells in the presence of 5-FC, HB1.F3.CD and HB1.F3.CD.IFN-β cells exhibited the cytotoxicity on HT-29 cells via the bystander effect. In particular, HB1.F3.CD.IFN-β cells showed the synergistic cytotoxic activity of 5-FU and IFN-β. We also confirmed the migration ability of HB1.F3.CD and HB1.F3.CD.IFN-β cells toward HT-29 cells by a modified migration assay in vitro, where chemoattractant factors secreted by HT-29 cells attracted the GESTECs. In a xenograft mouse model, the volume of tumor mass was decreased up to 56% in HB1.F3.CD injected mice while the tumor mass was greatly inhibited about 76% in HB1.F3.CD.IFN-β injected mice. The therapeutic treatment by these GESTECs is a novel strategy where the combination of the migration capacity of stem cells as a vector for therapeutic genes towards colorectal cancer and a synergistic antitumor effect of CD and IFN-β genes can selectively target this type of cancer.