Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01034 (cystatin C)
 3,397 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We found IL-6-STAT3 pathway suppresses MHC class II (MHCII) expression on dendritic cells (DCs) and attenuates T cell activation. Here, we showed that IL-6-STAT3 signaling reduced intracellular MHCII alphabeta dimmer, Ii, and H2-DM levels in DCs. IL-6-mediated STAT3 activation decreased cystatin C level, an endogenous inhibitor of cathepsins, and enhanced cathepsin activities. Importantly, cathepsin S inhibitors blocked reduction of MHCII alphabeta dimer, Ii, and H2-DM in the IL-6-treated DCs. Overexpression of cystatin C suppressed IL-6-STAT3-mediated increase of cathepsin S activity and reduction of MHCII alphabeta dimer, Ii, and H2-DM levels in DCs. Cathepsin S overexpression in DCs decreased intracellular MHCII alphabeta dimer, Ii, and H2-DM levels, LPS-mediated surface expression of MHCII and suppressed CD4(+) T cell activation. IL-6-gp130-STAT3 signaling in vivo decreased cystatin C expression and MHCII alphabeta dimer level in DCs. Thus, IL-6-STAT3-mediated increase of cathepsin S activity reduces the MHCII alphabeta dimer, Ii, and H2-DM levels in DCs, and suppresses CD4(+) T cell-mediated immune responses.
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PMID:IL-6-STAT3 controls intracellular MHC class II alphabeta dimer level through cathepsin S activity in dendritic cells. 1628 17

The cysteine protease cathepsin S is highly expressed in malignant tissues. By using a mouse model of multistage murine pancreatic islet cell carcinogenesis in which cysteine cathepsin activity has been functionally implicated, we demonstrated that selective cathepsin S deficiency impaired angiogenesis and tumor cell proliferation, thereby impairing angiogenic islet formation and the growth of solid tumors, whereas the absence of its endogenous inhibitor cystatin C resulted in opposite phenotypes. Although mitogenic vascular endothelial growth factor, transforming growth factor-beta1, and the anti-angiogenic endostatin levels in either serum or carcinoma tissue extracts did not change in cathepsin S- or cystatin C-null mice, tumor tissue basic fibroblast growth factor and serum type 1 insulin growth factor levels were higher in cystatin C-null mice, and serum type 1 insulin growth factor levels were also increased in cathepsin S-null mice. Furthermore, cathepsin S affected the production of type IV collagen-derived anti-angiogenic peptides and the generation of bioactive pro-angiogenic gamma2 fragments from laminin-5, revealing a functional role for cathepsin S in angiogenesis and neoplastic progression.
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PMID:Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors. 1636 41

Cystatin C (CST3) is a secreted inhibitor of lysosomal cysteine proteases cathepsins B (CTSB) and CTSL, which are abundant in the ovine endometrium and conceptus. In mice, cathepsins and cystatins play important roles in implantation and placentation. This study determined effects of the estrous cycle, pregnancy, progesterone (P4), and interferon-tau (IFNT) on CST3 in the ovine uterus. In cyclic ewes, CST3 mRNA was low on d 10, increased about 12-fold by d 12, and declined thereafter. In early pregnant ewes, CST3 mRNA was low on d 10 and increased about 130-fold from d 10 to d 20. CST3 mRNA and protein were abundant in the endometrial luminal epithelium (LE) and glandular epithelium and also in conceptus trophectoderm. In uterine flushes from pregnant ewes, CST3 protein was not detected on d 10 but was abundant on d 12, 14, and 16. In another study, treatment of ovariectomized, cyclic ewes with P4 induced a 14-fold increase in endometrial CST3 mRNA, and IFNT stimulated an additional 2-fold increase in CST3 mRNA in P4-treated ewes but not in ewes treated with P4 and the antiprogestin ZK 136,317. CST3 mRNA and protein were abundant in the endometrial luminal epithelium and superficial glandular epithelium of P4-treated ewes but were very low or not detectable in endometria of P4- and ZK-treated ewes. These results indicate that CST3 is a novel P4-induced and IFNT-stimulated gene expressed only in the epithelial cells of the ovine endometrium and implicate CST3 in regulation of uterine cathepsin activity during conceptus implantation.
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PMID:Progesterone and interferon-tau regulate cystatin C in the endometrium. 1655 62

Between 1998 and 1999 we suggested a role for cysteine proteases, particularly cathepsins S and K, in atherosclerosis and abdominal aortic aneurysm (AAA) formation. We also demonstrated the presence and activity of cathepsins S, K, and L in atherosclerotic and aneurysmal lesions in humans. Features unique to this family of extracellular enzymes indicate its likely participation in these vascular diseases. As very potent elastolytic enzymes, cathepsins are strong candidates as key participants in aneurysm development. Importantly, cathepsins express very high elastolytic activity in AAA due to reciprocal correlation with cystatin C, their most abundant endogenous inhibitor. Two opposite processes coexist in aneurysmal tissue: overexpression of elastolytic cathepsins, and severe suppression of cystatin C, probably due to differentially regulated expression and secretion of cathepsins and their inhibitors in response to inflammatory cytokines. Involvement of cathepsins in microvessel formation, a pathophysiological marker of human AAA, and programmed cell death (apoptosis), increases the likelihood of cathepsin participation in AAA formation and growth. We also summarize here results obtained in our and other laboratories that demonstrated reduced atherosclerosis and AAA in in vivo models using mice lacking different cathepsins. Deficiency of cysteine protease inhibitor cystatin C in atherosclerosis-prone ApoE-null mice leads to the development of specific features of AAA such as thinning of the tunica media and aortic dilatation. Taken together, such findings in humans in vitro with different cell types and in vivo in genetically altered mice demonstrate the importance of cysteine protease/protease inhibitor balance in dysregulated arterial integrity and remodeling during atherosclerosis and aortic aneurysm formation.
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PMID:Do cathepsins play a role in abdominal aortic aneurysm pathogenesis? 1718 32

Cystatin C, known as an inhibitor of the cathepsin family of cysteine proteases, has been evaluated in several cardiovascular disorders such as atherosclerosis and acute myocardial infarction. The potential interaction between transforming growth factor-beta1 and cystatin C has also been demonstrated in some cell types. Accordingly, we aimed to compare the plasma levels of cystatin C and transforming growth factor-beta1 in patients with coronary artery ectasia coexisting with coronary artery disease and those with coronary artery disease alone. Thirty-nine patients with coronary artery ectasia and coronary artery disease and 35 age and sex-matched patients with coronary artery disease alone were prospectively enrolled in the study. Blood samples of all patients and control participants for measuring plasma cystatin C and transforming growth factor-beta1 levels were drawn>or=24 h after the coronary angiography. Cystatin C concentrations in plasma were measured by latex-enhanced reagent on a Behring Nephelometer II. Plasma levels of transforming growth factor-beta1 were measured by using transforming growth factor-beta1 enzyme-linked immunosorbent assay kit (BioSource International, Inc., Camarillo, California, USA). Plasma level of cystatin C was significantly higher in patients with coronary artery ectasia+coronary artery disease than in patients with coronary artery disease alone (1.05+/-0.30 mg/dl vs. 0.92+/-0.18 mg/mdl, P=0.025, respectively). Transforming growth factor-beta1 was also found to be significantly higher in patients with coronary artery ectasia+coronary artery disease compared with those with coronary artery disease (2.47+/-0.43 vs. 2.22+/-0.43 pg/ml, P=0.02, respectively). The plasma level of cystatin C was significantly but weakly correlated with that of transforming growth factor-beta1 (r=0.217 P=0.02). We conclude that plasma levels of cystatin C and transforming growth factor-beta1 are significantly higher in patients with combined coronary artery ectasia and coronary artery disease than in those with coronary artery disease. Correlation between transforming growth factor-beta1 and cystatin C may also suggest that pathogenesis of coronary artery ectasia might have some different pathways from atherosclerosis with respect to the regulation of extracellular matrix remodeling. Therefore, the role of cystatin in the pathogenesis of coronary artery ectasia and its potential interaction with transforming growth factor-beta1 should be evaluated in further studies.
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PMID:Increased plasma levels of cystatin C and transforming growth factor-beta1 in patients with coronary artery ectasia: can there be a potential interaction between cystatin C and transforming growth factor-beta1. 1742 95

Cystatin C and cathepsins could play a role in almost all processes involved in atherosclerotic lesion formation by their degradation of extracellular matrix proteins and apolipoprotein B100, the protein moiety of LDL. Several cysteine cathepsins are upregulated in human lesions accompanied by a decrease in cystatin C, the major inhibitor of cysteine cathepsins. Recent research show that atherosclerotic mice deficient in cystatin C display increased elastic lamina degradation as well as larger plaque formation. Cathepsin S- and K-deficient atherosclerotic mice, on the other hand, both have less atherosclerosis, where cathepsin S-/- mice exhibited fewer plaque ruptures and cathepsin K-/- larger foam cells than control mice. This article reviews possible roles of cystatin C and cathepsins in different processes and stages of the atherosclerotic disease.
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PMID:Cystatin C and cathepsins in cardiovascular disease. 1850 21

Cystatin C, an endogenous inhibitor of cathepsin proteases has emerged as a biomarker of cardiovascular risk and reduced renal function. Epidemiological studies indicate that serum cystatin C increased in human obesity. Here, we evaluated the contribution of adipose tissue to this elevation, based on our previous observation that cystatin C is produced by in vitro differentiated human adipocytes. We measured serum cystatin C in 237 nonobese (age: 51 +/- 0.8 years; BMI: 22.8 +/- 0.11 kg/m(2)) and 248 obese subjects (age: 50 +/- 0.8 years; BMI: 34.7 +/- 0.29 kg/m(2)). Creatinine-based estimated glomerular filtration rate (eGFR) was calculated to account for renal status. Cystatin C gene expression and secretion were determined on surgical adipose tissue biopsies in a distinct group of subjects. Serum cystatin C is elevated in obese subjects of both genders, independently of reduced eGFR. Cystatin C mRNA is expressed in subcutaneous and omental adipose tissue, at twice higher levels in nonadipose than in adipose cells. Gene expression and cystatin C release by adipose tissue explants increase two- to threefold in obesity. These data confirm elevation of serum cystatin C in human obesity and strongly argue for a contribution of increased production of cystatin C by enlarged adipose tissue. Because cystatin C has the potential to affect adipose tissue and vascular homeostasis through local and/or systemic inhibition of cathepsins, this study adds a new factor to the list of adipose tissue secreted bioactive molecules implicated in obesity and obesity-linked complications.
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PMID:Potential contribution of adipose tissue to elevated serum cystatin C in human obesity. 2262 76

Dendritic cells (DCs) play a key role in the pathogenesis of HIV infection. HIV interacts with these cells through 2 pathways in 2 temporal phases, initially via endocytosis and then via de novo replication. Here the transcriptional response of human DCs to HIV-1 was studied in these phases and at different stages of the virus replication cycle using purified HIV-1 envelope proteins, and inactivated and viable HIV-1. No differential gene expression was detected in response to envelope. However, more than 100 genes were differentially expressed in response to entry of viable and inactivated HIV-1 in the first phase. A completely different set of genes was differentially expressed in the second phase, predominantly in response to viable HIV-1, including up-regulation of immune regulation genes, whereas genes encoding lysosomal enzymes were down-regulated. Cathepsins B, C, S, and Z RNA and protein decreased, whereas cathepsin L was increased, probably reflecting a concomitant decrease in cystatin C. The net effect was markedly diminished cathepsin activity likely to result in enhanced HIV-1 survival and transfer to contacting T lymphocytes but decreased HIV-1 antigen processing and presentation to these T cells.
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PMID:HIV-1-infected dendritic cells show 2 phases of gene expression changes, with lysosomal enzyme activity decreased during the second phase. 1943 54

The balance between trophoblast cathepsin and decidual cystatin C expression is pivotal in physiological trophoblast development. Defective trophoblast invasion is characteristic of preeclampsia and may involve derangement of the cathepsin/cystatin C balance. We conducted a prospective nested case-control study of healthy women with singleton pregnancies in the first trimester of pregnancy. Maternal serum cystatin C concentrations in those subsequently developing preeclampsia (n = 30) were compared to controls with normal outcome (n = 90). The median cystatin C concentration in early pregnancy was significantly higher (P = .0001) in those who subsequently developed preeclampsia (median 0.65 mg/L) when compared to normal pregnancy (median 0.57 mg/L). Of the 30 women developing preeclampsia, 14 (47%) had cystatin C above the 80th centile (0.67 mg/L) for the controls. Maternal serum cystatin C concentrations in early pregnancy may be of value in identifying women at high risk of developing preeclampsia.
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PMID:Raised maternal serum cystatin C: an early pregnancy marker for preeclampsia. 1943 62

Given the increasing prevalence of human obesity worldwide, there is an urgent need for a better understanding of the molecular mechanisms linking obesity to metabolic and cardiovascular diseases. Our knowledge is nevertheless limited regarding molecules linking adipose tissue to downstream complications. The importance of cathepsins was brought to light in this context. Through a large scale transcriptomic analysis, our group recently identified the gene encoding cathepsin S as one of the most deregulated gene in the adipose tissue of obese subjects and positively correlated with body mass index. Other members of the cathepsin family are expressed in the adipose tissue, including cathepsin K and cathepsin L. Given their implication in atherogenesis, these proteases could participate into the well established deleterious relationship between enlarged adipose tissue and increased cardiovascular risk. Here, we review the clinical and experimental evidence relevant to the role of cathepsins K, L and S and their most abundant endogenous inhibitor, cystatin C, in atherosclerosis and in obesity.
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PMID:Cathepsins and cystatin C in atherosclerosis and obesity. 2041 81


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