IL6ST regulates liver tumorigenesis via the regulation of mitophagy

Hwan Ma,Jeong-Su Park,Feng Wang,Yeo-Jin Lee,Gyu-Rim Lee,Ekihiro Seki,Hwan-Soo Yoo,Yoon-Seok Roh 한국실험동물학회 2021 한국실험동물학회 학술발표대회 논문집 Vol.2021 No.7

Hepatocellular carcinoma (HCC) is the sixth most commonly occurring cancer in the world and the third largest cause of cancer mortality. There is increasing evidence that the inflammatory process is inherently associated with many different cancer types, including HCC. Cytokines are released in response to a diverse range of cellular stresses, including carcinogen-induced injury, infection, and inflammation. A number of cytokines that are produced in the tumor microenvironment have an important role in cancer pathogenesis. Among them, there are IL-6 family cytokines that share the common receptor subunit IL6ST. IL6ST regulates cell survival, growth, and proliferation through the regulation of JAK-Stat3 and PI3K-mTORC1. Both downstream pathways have been linked with autophagy and mitochondrial function. Moreover, mitophagy contributes to metabolic dysfunction syndrome and chronic liver diseases such as NAFLD, NASH, and HCC. However, the mechanism of how IL6ST modulates hepatocyte mitophagy and HCC development remains unclear. IL6ST activated Stat3 and mTORC1 signaling in HCC, as evidenced by the controls phosphorylation of Stat3 (Tyr705), P70S6K(T389), EIF4E(S209), and RPS6(S235). Interestingly, IL6ST prevents mitochondrial stress and improves cell viability by inhibition of Stat3 and mTORC1-ULK1 mediated mitophagy and apoptosis. In genetically engineered mouse models of HCC (TAK1ΔHep), hepatocyte-specific deletion of IL6ST suppressed the multiplicity and maximum size of naturally occurring cancer. In conclusion, IL6ST governs parallel activation of carcinogenic STAT3 along with mTORC1 in the pathogenesis of HCC by regulation of mitophagy-dependent apoptosis and cancer cell survival.

족삼리(足三里)의 전침자극(電鍼刺戟)이 흰쥐의 중추신경계(中樞神經系)에서 Interleukin-6 의 활성(活性)에 미치는 영향(影響) -구심성(求心性) 체감각(體感覺) 정보전달(情報傳達)을 중심(中心)으로-

이혜정,신형철,진수희,손양선,윤동학,임사비나,Lee, Hye-Jung,Shin, Hyung-Cheul,Jin, Soo-Hee,Son, Yang-Son,Yun, Dong-Hak,Lim, Sabina 대한침구의학회 2000 대한침구의학회지 Vol.17 No.4

Objectives : Acupuncture is expected to have somewhat like the efficacy parallel increasing activity of immune system in Western modem medicine. There, already, are many animal researches on activating effect of acupuncture for the immune system in peripheral organs. So, we carried out this experiment to see whether acupuncture has controlling effect on interleukin-6(IL-6) activity in rat's brain. Methods and Results : We had topical application of IL-6(1U=lpg, $10{\mu}l$) on brain of rat. It reduced afferent sensory transmission to the primary somatosensory(SI) cortex from periphery. Whereas, electrical stimulation(ES, 2Hz, 1.5V, 15min) of ST36(足三里) with application of IL-6 prominently activated afferent sensory transmission. ES of non-acupoint(proximal tail) with IL-6 showed suppression of afferent transmission. ES of ST36 without IL-6 application also exerted facilitation of afferent transmission to the SI cortex. Conclusions : Electoacupuncture(EA) on ST36 has noticeable influences on modulating activation of IL-6 in central nervous system, which do major role in immune system.

足三里의 電鍼刺戟이 흰쥐의 中樞神經系에서 Interleukin-6의 活性에 미치는 影響 - 求心性 體感覺 情報傳達을 中心으로- : 求心性 體感覺 情保傳達을 중심으로

이혜정,신형철,진수희,손양선,윤동학,임사비나 경희대학교 동서의학연구소 2001 東西醫學硏究所 論文集 Vol.2000 No.-

Objectives : Acupuncture is expected to have somewhat like the efficacy parallel increasing activity of immune system in Western modern medicine. There, already, are many animal researches on activating effect of acupuncture for the immune system in peripheral organs. So, we carried out this experiment to see whether acupuncture has controlling effect on interleukin-6(IL-6) activity in rat's brain. Methods and Results : We had topical application of IL-6(1U-1pg, 10㎕) on brain of rat. It reduced afferent sensory transmission to the primary somatosensory(SI) cortex from periphery. Whereas, electrical stimulation(ES, 2Hz, 1.5V, 15min) of ST36(足三里) with application of IL-6 prominently activated afferent sensory transmission. ES of non-acupoint(proximal tail) with IL-6 showed suppression of afferent transmission. ES of ST36 without IL-6 application also exerted facilitation of afferent transmission to the SI cortex. Conclusions : Electoacupuncture(EA) on ST36 has noticeable influences on modulating activation of IL-6 in central nervous system, which do major role in immune system.

鳥藥順氣散 藥針이 Rat의 Adjuvant 關節炎에 미치는 影響

河智容,李膳求,劉炳吉 대한동의병리학회 2000 동의생리병리학회지 Vol.14 No.2

최근 식생활의 변화, 운동부족, 평균연령의 증가 등의 여러 요인에 의하려 류마토이드 關節炎, 통풍성 關節炎, 골 關節炎 등의 관절질환이 늘어나고 있는 실정이다. 미국의 경우는 전국민의 2-3%가 關節炎에 이환 된 것으로 보고되고 있으며, 關節炎치료에 대한 硏究가 활발히 이루어지고 있다. 독일, 스위스, 일본 등 선진 여러 나라에서도 그 실태는 미국과 유사하며, 여러 연구기관에서 다방면의 硏究를 수행하고 있다. 烏藥順氣散은 ‘治一切風疾, 先服此, 疎通氣道, 進以風藥, 이치탄탄 , 及歷節風’治療효능이 있는 處方으로, 臨床的으로 많이 사용되고 있느나, 關節炎 모형에 대한 實驗的 硏究는 아직 시행되어 있지 않았다. 본 硏究는 實驗的으로 유발된 關節炎에 烏藥順氣散 약침을 犢鼻穴에 처치하여 나타난 결과이다. 1. 식염수로 처리한 대조군의 후족 용적은 0.62±0.11㎜를 나타냈고 烏藥順氣散처리군은 0.47±0.07㎜로 부종의 용적이 유의성 있게 억제되었다(P<0.05). 2. 정상군(Normal group)의 경우 백혈구 총수는 8.24±0.51(103/㎖), 식염수로 처리한 대조군의 백혈구 총수는 27.35±3.51(103㎖) 이었다. 烏藥順氣散처리군은 19.78±4.99(103㎖)로 대조군 보다 낮은 수치를 보여 關節炎 치료에 효과를 보였다(P<0.05). 3. TNF-α의 경우는 정상군에서 극히 소량의 m-RNA가 검출되어 염증 유발군과 비교해 볼 때 상당히 차이를 나타냈다. 염증유발군간에는 대조군이 약침처리군 보다 band의 size가 크고 선명하여 TNF-α의 량이 많음을 나타내어 염증 상태가 보다 더 심각함을 보여 주었다. 4. IL-6는 정상군에서 극히 소량으로 검출 되었으나 염증유발군에서는 상당한 크기로 선명하게 검출되어 염증상태가 심각함을 보여 주었다. 5. 조직 검사 결과 대조군에서는 염증반응이 심하게 나타나 조직의 형태가 매우 불규칙하고 다수의 염증 세포 등이 보였고 烏藥順氣散 약침처리군은 조직이 다소 회복된 상태의 증후가 보이고 염증세포의 수가 줄고 염증상태가 억제됨을 알수 있었다. 이상의 결과를 종합하여 보면 烏藥順氣散의 犢鼻穴 藥針 처리가 Freun's complete adjuvant 關節炎 유발 rat에 작용하여 염증을 억제한 것을 알 수 있었다. 그러나 이러한 효과에 대한 좀더 지속적인 연구가 필요하다고 생각한다. Effects of Oyaksunkisan acua-acupuncture on Adjuvant Arthritis in rats. The study was carried out to investigate the effects of aqua-acupuncture with Oyaksunkisan on the counts of Edema, WBC and m-RNA level of TNF-α, IL-6and COX-2 in rat with Freund's adjuvant arthritis. The size of edema showed a tendency to increased in the group of Freund's adjuvant arthristis compared with those of normal condition. In the groups of Freund's adjuvant arthristis, the size of edema showed hight in the control group compared with those of aqua-acupuncture group. The counts of WBC showed a tendency to increase in rat with Freund's adjuvant arthristis compared with those of normal condition, In the groups of Freund's adjuvant arthristis, the counts of WBC showed hight in control group compared with aqua-acupuncture group. In the RT-PCR, the mRNA of TNF-α, IL-6 and COX-2 were detected very low level in the normal condition compared with those of Freund's adjuvant arthristis. However in the groups of Freund's arthristis, the values showed no difference. In histological finding, because of severe inflammatory reaction, remarkably irregular tissue and large amount of inflammatory cells were found in the control group. But the aqua-acupuncture with Oyaksunkisan group showed small amount of inflammatory cells, the refrained inflammatory state and even recovering state. From these results, it is showed Oyaksunkisan acua-acupuncture refrain inflammatory reaction and muscular tissue necrosis in DS rats paw were induced by Freund's complete adjuvant. Effects of Oyaksunkisan acua-acupuncture on Adjuvant Arthritis in rats. The study was carried out to investigate the effects of aqua-acupuncture with Oyaksunkisan on the counts of Edema, WBC and m-RNA level of TNF-α, IL-6and COX-2 in rat with Freund's adjuvant arthritis. The size of edema showed a tendency to increased in the group of Freund's adjuvant arthristis compared with those of normal condition. In the groups of Freund's adjuvant arthristis, the size of edema showed hight in the control group compared with those of aqua-acupuncture group. The counts of WBC showed a tendency to increase in rat with Freund's adjuvant arthristis compared with those of normal condition, In the groups of Freund's adjuvant arthristis, the counts of WBC showed hight in control group compared with aqua-acupuncture group. In the RT-PCR, the mRNA of TNF-α, IL-6 and COX-2 were detected very low level in the normal condition compared with those of Freund's adjuvant arthristis. However in the groups of Freund's arthristis, the values showed no difference. In histological finding, because of severe inflammatory reaction, remarkably irregular tissue and large amount of inflammatory cells were found in the control group. But the aqua-acupuncture with Oyaksunkisan group showed small amount of inflammatory cells, the refrained inflammatory state and even recovering state. From these results, it is showed Oyaksunkisan acua-acupuncture refrain inflammatory reaction and muscular tissue necrosis in DS rats paw were induced by Freund's complete adjuvant.

足三里 電鍼이 흰쥐의 老化에 미치는 影響

이준성,임윤경,김영일 대한침구의학회 2007 대한침구의학회지 Vol.24 No.3

다양한 약침제제(藥鍼製劑)가 Rat의 Adjuvant 관절염(關節炎)에 미치는 영향(影響)

하지용,이선구,유병길,Ha, Jee-Yong,Lee, Seon-Goo,Yu, Byeong-Gil 대한약침학회 2000 Journal of pharmacopuncture Vol.3 No.2

To investigate effects of vanous herbal-acupuncture, which were Daebangpungtang, Oyaksungisan, Dokhwalgisaengtang, and Binsosan on Adjuvant Arthritis in rats, the edema rate, the number of WBC, the quantity of TNF-${\alpa}$, COX -2, and IL-6, and histological test of the muscular tissue were measured in the arthritis part. After elicilating arthritis of Sprague Dawely(SD) rats by injection of Freund's complets adjuvant for 2 weeks, saline was injected for the control group, Daebangpungtang acua-acupuncture was injected for the Daebangpungtang group, Oyaksungisan acua-acupuncture was injected for the Oyaksungisan group, Dokhwalgisaengtang acua-acupuncture was injected for the Dokhwalgisaengtang group, and Binsosan acua-acupuncture was injected for the Binsosan group during 30days. Selected point was ST35 in all groups. 1. The number of WBC was $8.24{\pm}0.51$($10^3$/ml) in the normal group and $27.35{\pm}3.51$($10^3$/ml) in the control group. the Daebangpungtang group and the Oyaksungisan group decreased each $20.42{\pm}2.75$($10^3$/ml) and $19.78{\pm}4.99$($10^3$/ml) in the Exp.ll group. This fact showed that the group Exp.ll was more effective than the control group effectively. (P<0.05) 2. The volume of the paw were checked. The volume of paw was $0.62{\pm}0.11mm in the control group and $0.45{\pm}0.08$mm in the Daebangpungtang group and $0.47{\pm}0.07$mm in the Oyaksungisan group, the swelling of the paw was restricted significantly in the Daebangpungtang and Oyaksungisan group(P<0.05) 3. The bands of the TNF-${\alpa}$, COX -2 in the muscular tissue of the control group wcre certain and thick than other groups(except normal group), and the band of the IL-6 in the muscular tissue of all group(except normal group) were similar forms. 4. In histological finding, because of severe inflammatory reaction, remarkably irregular tissue and large amount of inflammatory cells were found in thc control and Dokhwalgisaengtang group. But the Oyaksungisan and Daebangpul1gtang group showed small amount of inflammatory cells, the refrained inflammatory state and even recovering state. From these results, it is showed Oyaksugisan and Daebangpungtang acua-acupuncturc refrain inflammatory reaction and muscular tissue necrosis in SD rats paw were induced by Freund's complete adjuvant