포스터 발표 : 담관내 성장형과 비담관내 성장형 담관상피암종에서 matrix metalloproteinase-2 와 -9 및 tissue inhibitor of metalloproteinase-1 과 2 발현

채광조,라선영,오봉경,구자승,김영주,박찬일,박영년 대한간학회 2003 Clinical and Molecular Hepatology(대한간학회지) Vol.9 No.3(S)

Background/Aims: The intraductal growth (IG) type of cholangiocarcinoma has a better prognosis than the mass forming (MF) and periductal infiltrating (PI) types. Matrix metalloproteinase (MMP)-2 and MMP-9, regulated by tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-1, respectively, play important roles in the degradation of the basement membrane during tumor invasion. Alteration in MMPs and TIMPs may regulate the gross morphology of cholangiocarcinoma. Methods: MMP-2 and MMP-9 were analyzed in 22 cholangiocarcinomas with fresh tissue using zymography and real time quantitative RT-PCR, and expressions of MMP-2, MMP-9, TIMP-1 and TIMP-2 were evaluated in 76 cholangiocarcinomas by immunohistochemistry. Results: The total MMP-2, active 62 kDa MMP-2, and MMP-2 mRNA increased 5.6 and 8.0 times, 5.3 and 7.9 times, and 3.1 and 6.8 times in the MF and PI types, respectively, compared to the IG type. The MMP-9 was present in the proform without activation and revealed no significant difference in relation to the gross types. The balanced expressions of MMP-2/TIMP-2 and MMP-9/TIMP-1 were significantly decreased in the MF and PI types, compared to the IG type. In the non-neoplastic liver, the expressions of MMP-2 and MMP-9 were very low without active form. Conclusions: The activities of MMP-2 and loss of balanced expressions of MMP-2/TIMP-2 and MMP-9/TIMP-1 were increased in the MF and PI types with invasive growth compared to the IG type with a preserved basement membrane. MMP-2 and imbalance between MMPs and TIMPs are suggested to play important roles in invasive growth related to the gross type of cholangiocarcinoma

Regulation of expression of matrix metalloproteinase-9 by JNK in Raw 264.7 cells: presence of inhibitory factor(s) suppressing MMP-9 induction in serum and conditioned media

Yun-Song Lee,Huong Thi Lan Tran,Quang Van Ta 생화학분자생물학회 2009 Experimental and molecular medicine Vol.41 No.4

Matrix metalloproteinase-9 (MMP-9) secreted from macrophages plays an important role in tissue destruction and inflammation through degradation of matrix proteins and proteolytic activation of cytokines/ chemokines. Whereas the MEK-ERK and PI3KAkt pathways up-regulate MMP-9 expression, regulation of MMP-9 by JNK remains controversial. Presently, we aimed to determine the role of JNK in MMP-9 regulation in Raw 264.7 cells. Inhibition of JNK by the JNK inhibitor SP600125 induced MMP-9 in the absence of serum and suppressed the expression of TNF-α, IL-6 and cyclooxygenase-2 in LPS-treated Raw 264.7 cells. In a knockdown experiment with small interfering RNA, suppression of JNK1 induced MMP-9 expression. Interestingly, mouse serum suppressed SP600125- mediated MMP-9 induction, similar to IFN-γ. However, the inhibitory activity of mouse serum was not affected by pyridone 6, which inhibits Janus kinase downstream to IFN-γ. In addition to mouse serum, conditioned media of Raw 264.7 cells contained the inhibitory factor(s) larger than 10 kDa, which suppressed SP600125- or LPS-induced MMP-9 expression. Taken together, these data suggest that JNK1 suppresses MMP-9 expression in the absence of serum. In addition, the inhibitory factor(s) present in serum or secreted from macrophages may negatively control MMP-9 expression. Matrix metalloproteinase-9 (MMP-9) secreted from macrophages plays an important role in tissue destruction and inflammation through degradation of matrix proteins and proteolytic activation of cytokines/ chemokines. Whereas the MEK-ERK and PI3KAkt pathways up-regulate MMP-9 expression, regulation of MMP-9 by JNK remains controversial. Presently, we aimed to determine the role of JNK in MMP-9 regulation in Raw 264.7 cells. Inhibition of JNK by the JNK inhibitor SP600125 induced MMP-9 in the absence of serum and suppressed the expression of TNF-α, IL-6 and cyclooxygenase-2 in LPS-treated Raw 264.7 cells. In a knockdown experiment with small interfering RNA, suppression of JNK1 induced MMP-9 expression. Interestingly, mouse serum suppressed SP600125- mediated MMP-9 induction, similar to IFN-γ. However, the inhibitory activity of mouse serum was not affected by pyridone 6, which inhibits Janus kinase downstream to IFN-γ. In addition to mouse serum, conditioned media of Raw 264.7 cells contained the inhibitory factor(s) larger than 10 kDa, which suppressed SP600125- or LPS-induced MMP-9 expression. Taken together, these data suggest that JNK1 suppresses MMP-9 expression in the absence of serum. In addition, the inhibitory factor(s) present in serum or secreted from macrophages may negatively control MMP-9 expression.

Matrix Metalloproteinase-9 in Monocytic Myeloid-Derived Suppressor Cells Correlate with Early Infections and Clinical Outcomes in Allogeneic Hematopoietic Stem Cell Transplantation

Lee, Sung-Eun,Lim, Ji-Young,Kim, Tae Woo,Jeon, Young-Woo,Yoon, Jae-Ho,Cho, Byung-Sik,Eom, Ki-Seong,Kim, Yoo-Jin,Kim, Hee-Je,Lee, Seok,Cho, Seok-Goo,Kim, Dong-Wook,Lee, Jong Wook,Min, Woo-Sung,Shin, Do Elsevier 2018 Biology of blood and marrow transplantation Vol.24 No.1

<P><B>Abstract</B></P> <P>The recovery of myeloid-derived suppressor cells (MDSCs) and its relevance in clinical acute graft-versus-host disease (GVHD) and post-hematopoietic stem cell transplantation (HSCT) infections remain to be fully characterized. We examined the expansion of circulating monocytic (M-) MDSCs and granulocytic (G-) MDSCs at the time of engraftment in 130 patients undergoing allogeneic HSCT (allo-HSCT). Compared with the G-MDSC group, the high M-MDSC group had a higher infection rate within 100 days, along with worse 1-year cumulative incidence of treatment-related mortality (TRM) and 2-year probability of event-free survival (EFS). The frequency of M-MDSCs was associated with preceding severe mucositis. Transcriptome profiling analysis of 2 isolated MDSC subtype showed significantly greater <I>matrix metalloproteinase-9</I> (<I>MMP-9</I>) expression in M-MDSCs than in G-MDSCs. M-MDSCs produced abundantly more MMP-9. Importantly, compared with G-MDSCs, M-MDSCs isolated from patients post-HSCT had a greater capacity to suppress T cell responses, and MMP-9 blockade more forcefully inhibited their immunosuppressive effect. MMP-9 levels also were associated with the occurrence of infections and with transplantation outcomes. Based on these findings, we identify M-MDSCs as a major contributor to infections early after allo-HSCT and worse clinical outcomes via MMP-9.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Monocytic myeloid-derived suppressor cells (MDSCs), but not granulocytic MDSCs, affect clinical outcomes. </LI> <LI> Monocytic MDSCs produce more abundant matrix metalloproteinase-9 (MMP-9). </LI> <LI> Monocytic-MDSCs suppress T cells via MMP-9. </LI> <LI> MMP-9 levels are correlated with infections and transplantation outcomes. </LI> </UL> </P>

Correlation of expression and activity of matrix metalloproteinase-9 and -2 in human gingival cells of periodontitis patients

김경아,정수봉,노승현,송권호,김한나현,김철호,박영국 대한치주과학회 2013 Journal of Periodontal & Implant Science Vol.43 No.1

Purpose: Matrix metalloproteinases (MMPs) are capable of degrading extracellular matrix, and they are inducible enzymes depending on an inflammatory environment such as periodontitis and bacterial infection in periodontal tissue. Gingival inflammation has been postulated to be correlated with the production of MMP-2 and MMP-9. The objective of this study was to quantify the expression and activity of MMP-9 and -2, and to determine the correlation between activity and expression of these MMPs in human gingival tissues with periodontitis. Methods: The gingival tissues of 13 patients were homogenized in 500 μL of phosphate buffered saline with a protease inhibitor cocktail. The expression and activity of MMP-2 and -9 were measured by enzyme-linked immunosorbent assay and Western blot analysis, and quantified by a densitometer. For the correlation line, statistical analysis was performed using the Systat software package. Results: MMP-9 was highly expressed in all gingival tissue samples, whereas MMP-2 was underexpressed compared with MMP-9. MMP-9 activity increased together with the MMP-9 expression level, with a positive correlation (r=0.793, P=0.01). The correlation was not observed in MMP-2. Conclusions: The expression of MMP-2 and -9 might contribute to periodontal physiological and pathological processes, and the degree of MMP-9 expression and activity are predictive indicators relevant to the progression of periodontitis.

Effects of (-)-Epigallocatechin-3-gallate on Brain Infarction and the Activity Change of Matrix Metalloproteinase-9 Induced by Middle Cerebral Artery Occlusion in Mice

Qian, Yong-Ri,Kook, Ji-Hyun,Hwang, Shin-Ae,Kim, Do-Kyung,Kim, Jong-Keun The Korean Society of Pharmacology 2007 The Korean Journal of Physiology & Pharmacology Vol.11 No.3

Matrix metalloproteinases (MMPs) can degrade a wide range of extracellular matrix components. It has been reported that MMP-9 are activated after focal ischemia in experimental animals. (-)-Epigallocatechin-3-gallate (EGCG), a major constituent of green tea polyphenols, is a potent free radical scavenger and reduces the neuronal damage caused by oxygen free radicals. And it has been known that EGCG could reduce the infarction volume in focal brain ischemia and inhibit MMP-9 activity. To delineate the relationship between the anti-ischemic action and the MMP-9-inhibiting action of EGCG, we investigated the effect of EGCG on brain infarction and the activity of matrix metalloproteinase-9 induced by permanent middle cerebral artery occlusion (pMCAO) in ICR mice. EGCG (40 mg/kg, i.p. $15{\sim}30min$ prior to MCAO) significantly decreased infarction volume at 24 hr after MCAO. GM 6001 (50 mg/kg, i.p. $15{\sim}30min$ prior to MCAO), a MMP inhibitor, also significantly reduced infarction volume. In zymogram, MMP-9 activities began to increase at ipsilateral cortex at 2 hr after MCAO, and the increments of MMP-9 activities were attenuated by EGCG treatment. Western blot for MMP-9 also showed patterns similar to that of zymogram. These findings demonstrate that the anti-ischemic action of EGCG ire mouse focal cerebral ischemia involves its inhibitory effect on MMP-9.

Correlation of expression and activity of matrix metalloproteinase-9 and -2 in human gingival cells of periodontitis patients

Kim, Kyung-A,Chung, Soo-Bong,Hawng, Eun-Young,Noh, Seung-Hyun,Song, Kwon-Ho,Kim, Hanna-Hyun,Kim, Cheorl-Ho,Park, Young-Guk Korean Academy of Periodontology 2013 Journal of Periodontal & Implant Science Vol.43 No.1

Purpose: Matrix metalloproteinases (MMPs) are capable of degrading extracellular matrix, and they are inducible enzymes depending on an inflammatory environment such as periodontitis and bacterial infection in periodontal tissue. Gingival inflammation has been postulated to be correlated with the production of MMP-2 and MMP-9. The objective of this study was to quantify the expression and activity of MMP-9 and -2, and to determine the correlation between activity and expression of these MMPs in human gingival tissues with periodontitis. Methods: The gingival tissues of 13 patients were homogenized in $500{\mu}L$ of phosphate buffered saline with a protease inhibitor cocktail. The expression and activity of MMP-2 and -9 were measured by enzyme-linked immunosorbent assay and Western blot analysis, and quantified by a densitometer. For the correlation line, statistical analysis was performed using the Systat software package. Results: MMP-9 was highly expressed in all gingival tissue samples, whereas MMP-2 was underexpressed compared with MMP-9. MMP-9 activity increased together with the MMP-9 expression level, with a positive correlation (r=0.793, P=0.01). The correlation was not observed in MMP-2. Conclusions: The expression of MMP-2 and -9 might contribute to periodontal physiological and pathological processes, and the degree of MMP-9 expression and activity are predictive indicators relevant to the progression of periodontitis.

Effects of (⁣)-Epigallocatechin-3-gallate on Brain Infarction and the Activity Change of Matrix Metalloproteinase-9 Induced by Middle Cerebral Artery Occlusion in Mice

Yong Ri Qian,Ji Hyun Kook,Shinae Hwang,Do Kyung Kim,Jong-Keun Kim 대한생리학회-대한약리학회 2007 The Korean Journal of Physiology & Pharmacology Vol.11 No.3

Matrix metalloproteinases (MMPs) can degrade a wide range of extracellular matrix components. It has been reported that MMP-9 are activated after focal ischemia in experimental animals. (⁣)-Epigallocatechin-3-gallate (EGCG), a major constituent of green tea polyphenols, is a potent free radical scavenger and reduces the neuronal damage caused by oxygen free radicals. And it has been known that EGCG could reduce the infarction volume in focal brain ischemia and inhibit MMP-9 activity. To delineate the relationship between the anti-ischemic action and the MMP-9-inhibiting action of EGCG, we investigated the effect of EGCG on brain infarction and the activity of matrix metalloproteinase-9 induced by permanent middle cerebral artery occlusion (pMCAO) in ICR mice. EGCG (40 mg/kg, i.p. 15∼30 min prior to MCAO) significantly decreased infarction volume at 24 hr after MCAO. GM 6001 (50 mg/kg, i.p. 15∼30 min prior to MCAO), a MMP inhibitor, also significantly reduced infarction volume. In zymogram, MMP-9 activities began to increase at ipsilateral cortex at 2 hr after MCAO, and the increments of MMP-9 activities were attenuated by EGCG treatment. Western blot for MMP-9 also showed patterns similar to that of zymogram. These findings demonstrate that the anti-ischemic action of EGCG in mouse focal cerebral ischemia involves its inhibitory effect on MMP-9.

Correlation between the expression of matrix metalloproteinase 9 and the expression of tissue inhibitor of metalloproteinase-1 of uterosacral ligament in uterine prolapse

( Dhanny Primantara Johari Santoso ),( Benny Hasan Purwara ),( Eppy Darmadi Achmad ) 대한산부인과학회 2022 Obstetrics & Gynecology Science Vol.65 No.1

Objective This study aimed to analyze the correlation between the immunoexpression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TiMP1) in the uterosacral ligaments in patients with uterine prolapse. Methods This analytic-correlative cross-sectional study included 32 patients who were admitted at the Hasan Sadikin General Hospital from July to December 2013. Sixteen of the patients had uterine prolapse, while the rest did not. The patients underwent total hysterectomy, radical hysterectomy, or staging laparotomy. MMP-9 and TiMP1 expression in the uterosacral ligaments was measured via immunohistochemical staining. The median expression per field of view was calculated using a histoscore. Results MMP-9 expression in patients with uterine prolapse was found to be higher than that in the control group. Meanwhile, TiMP1 expression showed no significant difference between the groups. Spearman’s analysis showed a moderate correlation between the expression of MMP-9 and uterine prolapse incidence (P=0.02), with a correlation coefficient of 0.574. Conclusion There is a moderate correlation between MMP-9 expression and the incidence of uterine prolapse. It can be considered one of the primary etiologies of uterine prolapse.

Matrix Metalloproteinase-9 as a Prognostic Factor in Gastric Cancer: A Meta-Analysis

Zhang, Qiong-Wen,Liu, Lei,Chen, Ru,Wei, Yu-Quan,Li, Ping,Shi, Hua-Shan,Zhao, Yu-Wei Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.6

Background: Matrix metalloproteinase-9 (MMP-9) is associated with disruption of basement membranes of blood vessels and promotion of metastasis through the lymphatics. However, its prognostic value for survival in patients with gastric cancer remains controversial. Method: We therefore conducted a meta-analysis of the published literature in order to clarify the impact of MMP-9. Clinical studies were selected for further analysis if they provided an independent assessment of MMP-9 in gastric cancer and reported analysis of survival data according to MMP-9 expression. Results: A total of 11 studies, covering 1700 patients, were included for meta-analysis. A summary hazard ratio (HR) of all studies and sub-group hazard ratios were calculated. The combined HR suggested that a positive MMP-9 expression had an impact on overall survival: 1.25 (95% confidence interval 1.11-1.40) in all eligible studies; 1.13 (1.06-1.20) in 8 studies detecting MMP-9 by immunohistochemistry; 1.36 (1.12-1.65) in 7 studies from Asia. Only one study for DFS showed a significant impact on disease free survival (HR 1.73, 95%CI 1.27-2.34). Conclusions: Our findings suggested that MMP-9 protein expression might be a factor for a poor prognosis in patients with gastric cancer. However, the association was rather weak, so that more prospective studies should further explore the prognostic impact of MMP-9 mRNA and correlations between MMP-9 and clinicopathological characteristics.

내독소로 자극된 당뇨 쥐에서 단백분해효소와 그 억제제 발현

서기현 ( Ki Hyun Seo ),최재성 ( Jae Sung Choi ),나주옥 ( Joo Ok Na ),어수택 ( Soo Taek Uh ),김용훈 ( Yong Hoon Kim ),박춘식 ( Choon Sik Park ) 대한결핵 및 호흡기학회 2006 Tuberculosis and Respiratory Diseases Vol.61 No.3

연구배경: 급성폐손상에서 염증세포의 모집과 활성, 그 염증세포의 부산물인 활성산소, 사이토카인, 기질단백분해효소등과 기획성 세포사멸이 폐실질 파괴와 재구성에 중요한 역할을 하는 것으로 알려져 있다. 또한 당뇨환자에서 세균 감염 시 중성구의 기능 이상과 활성 산화기의 기능이상, 살균 능의 저하를 가져온다고 알려져 있으나 단백분해효소 대한 견해가 부족한 편이다. 본 연구에서는 동물 모델에서 내독소로 유발된 급성폐손상의 기전에 중요한 역할을 하는 단백분해효소와 그 억제제의 분비를 비교 관찰하였다. 방법: 생후 6주된 수컷 쥐 40마리를 정상군, 당뇨군, 내독소군, 당뇨-내독소군으로 나누어 당뇨군은 streptozotocin을 투여하였고 내독소군은 지질다당질을 투여하고서 희생시켰다. 각각 혈액, 기관지폐포세척액을 얻어 gelatin zymography를 이용하여 MMP-9의 활성을 측정하였고 Western blot으로 TIMP-1을 측정하였다. 결과: 1) 내독소군과 당뇨-내독소군은 정상과 당뇨군에 비해 폐 무게의 증가와 기관지폐포세척액과 폐 조직 소견상 염증세포, 특히 중성구의 증가를 보였고 기관지폐포세척액 내 단백질 양의 증가를 보였다 (p<0.05). 또한 당뇨-내독소군은 내독소군과 달리 기관지폐포세척액 내 총 염증세포 수가 유의하게 감소하였다 (p=0.001). 2) MMP-9의 활성은 혈청에서는 당뇨-내독소군이 다른 세 군보다 가장 높은 활성을 보였고 기관지폐포세척액에서는 내독소군과 당뇨-내독소군은 차이가 없었으나 정상과 당뇨군에 비해 높은 활성을 보였다 (p<0.05). TIMP-1 발현은 혈청에서는 네 군간의 차이가 없었고 기관지폐포세척액은 당뇨-내독소군이 가장 낮은 발현을 보였다 (p<0.05). MMP-9/TIMP-1 density ratio를 비교했을 때 기관지폐포세척액에서 당뇨-내독소군이 다른 세 군보다 높았고 내독소군도 정상과 당뇨군보다 높았다 (p<0.05). 결론: 급성폐손상이 있는 당뇨에서는 염증세포의 화학 주성 감소로 중증 감염에 민감해지고, 기질단백분해효소 활성 증가와 그 억제제의 감소로 폐손상이 가중될 것으로 예상된다. Background: An acute lung injury(ALI) is characterized by the recruitment, activation, and apoptosis of inflammatory cells, numerous products released by inflammatory cells such as reactive oxygen species, inflammatory mediators, and a variety of proteolytic enzymes. It was reported that bacterial infections in diabetics showed impaired PMN functions such as reduced PMN respiratory burst and decreased microbicidal activity in inflamed tissue. However, the effect of the proteinase-inhibitor (MMP-9 vs TIMP-1) in ALI in diabetics is unclear. This study evaluated the differences in the expression of MMP-9 and TIMP-1 after the stimulation of endotoxin in a rat model. Methods: Six-week-old male Sprague-Dawley rats were classified into normal, DM, LPS and DM+LPS groups. The peripheral blood, BAL fluids, and lung tissues were obtained from individual rats. The MMP-9 activity was measured by gelatin zymography and the TIMP-1 level was measured by Western blotting. Results: The total BAL cells of the DM-LPS groups were significantly lower than the LPS groups (p<0.01). The MMP-9 activities in the serum were higher in the DM+LPS groups than in the other groups. The MMP-9 activities in the BAL fluids were significantly higher in the DM+LPS group than in the normal and diabetic rats (p<0.05). TIMP-1 expressions in the BAL fluids were significantly lower in the DM+LPS group than other groups (p<0.05). The ratio between MMP-9 and TIMP-1 in the BAL fluids was significantly higher in the DM+LPS groups (p<0.05). Conclusion: In ALI in diabetics the higher MMP-9 activity and lower TIMP-1 level are believed to prolonged and intensify the course of inflammation. (Tuberc Respir Dis 2006; 61: 256-264)