Targeting kallikrein 6‐proteolysis attenuates CNS inflammatory disease

Blaber, Sachiko I.; Ćirić, Bogoljub; Christophi, George P.; Bernett, Matthew J.; Blaber, Michael; Rodriguez, Moses; Scarisbrick, Isobel A.

doi:10.1096/fj.03-1212fje

Cited by 89 publications

(138 citation statements)

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“…The most clearly established causes of ER stress- induced apoptosis involve protein mutations leading to protein misfolding, for example, the missense mutation in insulin 2 in the Akita mouse (35) and peripheral neuropathy as a result of mutations in the P0 protein (36). High expression rates of human IAPP in mice leads to the formation of toxic intracellular IAPP oligomers (37), implying misfolding and/or intracellular trafficking of human IAPP beyond a critical threshold of expression.…”

Section: Fig 5 Expression Of Perinuclear Chop and Insulin In Human mentioning

confidence: 99%

High Expression Rates of Human Islet Amyloid Polypeptide Induce Endoplasmic Reticulum Stress–Mediated β-Cell Apoptosis, a Characteristic of Humans With Type 2 but Not Type 1 Diabetes

et al. 2007

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OBJECTIVE-Endoplasmic reticulum (ER) stress-induced apoptosis may be a common cause of cell attrition in diseases characterized by misfolding and oligomerisation of amyloidogenic proteins. The islet in type 2 diabetes is characterized by islet amyloid derived from islet amyloid polypeptide (IAPP) and increased ␤-cell apoptosis. We questioned the following: 1) whether IAPP-induced ␤-cell apoptosis is mediated by ER stress and 2) whether ␤-cells in type 2 diabetes are characterized by ER stress. RESEARCH DESIGN AND METHODS-The mechanism of IAPP-induced apoptosis was investigated in INS-1 cells and human IAPP (HIP) transgenic rats. ER stress in humans was investigated by ␤-cell C/EBP homologous protein (CHOP) expression in 7 lean nondiabetic, 12 obese nondiabetic, and 14 obese type 2 diabetic human pancreata obtained at autopsy. To assure specificity for type 2 diabetes, we also examined pancreata from eight cases of type 1 diabetes.RESULTS-IAPP induces ␤-cell apoptosis by ER stress in INS-1 cells and HIP rats. Perinuclear CHOP was rare in lean nondiabetic (2.6 Ϯ 2.0%) and more frequent in obese nondiabetic (14.6 Ϯ 3.0%) and obese diabetic (18.5 Ϯ 3.6%) pancreata. Nuclear CHOP was not detected in lean nondiabetic and rare in obese nondiabetic (0.08 Ϯ 0.04%) but six times higher (P Ͻ 0.01) in obese diabetic (0.49 Ϯ 0.17%) pancreata. In type 1 diabetic pancreata, perinuclear CHOP was rare (2.5 Ϯ 2.3%) and nuclear CHOP not detected. B oth type 1 and type 2 diabetes are characterized by deficits in ␤-cell mass and increased ␤-cell apoptosis (1-6). The mechanism that initiates ␤-cell apoptosis in type 1 diabetes is believed to be autoimmune-mediated cytokine production (5). Several mechanisms have been proposed for increased ␤-cell apoptosis in type 2 diabetes, including oxygen free radicals (7), free fatty acid toxicity (8), interleukin-1␤ (9), and formation of islet amyloid polypeptide (IAPP) toxic oligomers (10 -12). CONCLUSIONS-ERProgrammed cell death, or apoptosis, is important in multicellular organisms to permit organ development and remodeling (13). In disease states, apoptosis permits selective removal of cells that are damaged, particularly in relation to cell cycle, so that damage is not propagated (3,14). Apoptosis may be initiated by a wide variety of cellular insults, which are currently thought to act through at least three pathways that converge to accomplish irreversible destruction of the cell's chromosomes. These three major pathways have been designated as the extrinsic and intrinsic pathways and endoplasmic reticulum (ER) stress pathway (15,16). The extrinsic pathway is classically exemplified by cytokine-induced cell death, mediated through cell surface death receptors (17). The intrinsic pathway is most often described as a response to mitochondrial disruption, for example, secondary to oxygen free radicals (18). ER stress-induced apoptosis is classically ascribed to aggregates of misfolded protein that are believed to compromise the ER membrane (15).The human pancreatic ␤-cell is vulnerable to al...

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Section: Fig 5 Expression Of Perinuclear Chop and Insulin In Human mentioning

confidence: 99%

High Expression Rates of Human Islet Amyloid Polypeptide Induce Endoplasmic Reticulum Stress–Mediated β-Cell Apoptosis, a Characteristic of Humans With Type 2 but Not Type 1 Diabetes

et al. 2007

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“…Additionally, while not fully elucidated, kallikreins likely participate in activation/inactivation cascades with other serine proteases [25] and, indeed, may be regulated by overlapping endogenous inhibitors such as α1-antichymotrypsin, α1-antitrypsin, and α2-macroglobulin [157]. Already, kallikrein 6 (K6), the most abundant kallikrein in CNS with preferential expression by neurons and oligodendroglia, has been shown to be upregulated at sites of active demyelination in MS lesions, in TMEV, and in EAE models [26,27,45,229]. Importantly, inhibiting K6 enzymatic activity delays the onset of disease and reduces clinical and histological signs in EAE.…”

Section: Tissuementioning

confidence: 99%

“…Importantly, inhibiting K6 enzymatic activity delays the onset of disease and reduces clinical and histological signs in EAE. Notably, disease attenuation parallels diminished Th1 responses, which points to a prominent role for K6 not only in lesion development but also in modulation of the inflammatory response [27]. Furthermore, it was recently demonstrated that kallikreins are not only capable of modifying the extracellular environment but, like other serine proteases, may serve in a hormone-like capacity by virtue of their ability to activate select PAR.…”

Section: Tissuementioning

confidence: 99%

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The Multiple Sclerosis Degradome: Enzymatic Cascades in Development and Progression of Central Nervous System Inflammatory Disease

Scarisbrick

2008

Current Topics in Microbiology and Immunology

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An array of studies implicate different classes of protease and their endogenous inhibitors in multiple sclerosis (MS) pathogenesis based on expression patterns in MS lesions, sera, and/or cerebrospinal fluid (CSF). Growing evidence exists regarding their mechanistic roles in inflammatory and neurodegenerative aspects of this disease. Proteolytic events participate in demyelination, axon injury, apoptosis, and development of the inflammatory response including immune cell activation and extravasation, cytokine and chemokine activation/inactivation, complement activation, and epitope spreading. The potential significance of proteolytic activity to MS therefore relates not only to their potential use as important biomarkers of disease activity, but additionally as prospective therapeutic targets. Experimental data indicate that understanding the net physiological consequence of altered protease levels in MS development and progression necessitates understanding protease activity in the context of substrates, endogenous inhibitors, and proteolytic cascade interactions, which together make up the MS degradome. This review will focus on evidence regarding the potential physiologic role of those protease families already identified as markers of disease activity in MS; that is, the metallo-, serine, and cysteine proteases.

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“…For example, hK5, -6, and -14 are found at increased levels in the serum and/or ascites fluid of ovarian cancer patients (22)(23)(24)(25)(26) as well as in the serum of breast cancer patients (23,26). Kallikreins are also highly expressed at sites of inflammation (27,28). However, despite their widespread expression in diseased tissues, the mechanisms whereby this enzyme family regulates cellular function are not clear.…”

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confidence: 99%

Proteinase-activated Receptors, Targets for Kallikrein Signaling

Οικονομοπούλου

Hansen

Saifeddine

et al. 2006

Journal of Biological Chemistry

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Serine proteinases like thrombin can signal to cells by the cleavage/activation of proteinase-activated receptors (PARs).Although thrombin is a recognized physiological activator of PAR 1 and PAR 4 , the endogenous enzymes responsible for activating PAR 2 in settings other than the gastrointestinal system, where trypsin can activate PAR 2 , are unknown. We tested the hypothesis that the human tissue kallikrein (hK) family of proteinases regulates PAR signaling by using the following: 1) a high pressure liquid chromatography (HPLC)-mass spectral analysis of the cleavage products yielded upon incubation of hK5, -6, and -14 with synthetic PAR N-terminal peptide sequences representing the cleavage/activation motifs of PAR 1 , PAR 2 , and PAR 4 ; 2) PAR-dependent calcium signaling responses in cells expressing PAR 1 , PAR 2 , and PAR 4 and in human platelets; 3) a vascular ring vasorelaxation assay; and 4) a PAR 4 -dependent rat and human platelet aggregation assay. We found that hK5, -6, and -14 all yielded PAR peptide cleavage sequences consistent with either receptor activation or inactivation/disarming. Furthermore, hK14 was able to activate PAR 1 , PAR 2 , and PAR 4 and to disarm/inhibit PAR 1 . Although hK5 and -6 were also able to activate PAR 2 , they failed to cause PAR 4 -dependent aggregation of rat and human platelets, although hK14 did. Furthermore, the relative potencies and maximum effects of hK14 and -6 to activate PAR 2 -mediated calcium signaling differed. Our data indicate that in physiological settings, hKs may represent important endogenous regulators of the PARs and that different hKs can have differential actions on PAR 1 , PAR 2 , and PAR 4 . Proteinase-activated receptors (PAR 1-4 )3 compose a unique family of four G-protein-coupled cell surface receptors for certain proteinases (1-9). Proteolytic cleavage within the extracellular N terminus reveals a tethered ligand that binds to the extracellular receptor domains to initiate cell signaling (5, 6, 9, 10). Proteinases that activate PARs include coagulation factors, enzymes from inflammatory cells, and proteinases from epithelial cells and neurons. These enzymes, generated and released during injury and inflammation, can cleave and activate PARs on many cell types from a variety of species (humans, rats, and mice) to regulate the critically important processes of hemostasis, inflammation, pain, and tissue repair. Other proteinases that cleave PARs downstream of the N-terminal tethered ligand sequence disable the receptors for further proteolytic activation, thus abrogating PAR signaling. It is of considerable interest to identify the proteinases that activate and/or disable PARs, in view of the emerging role that these receptors can play in diseases such as asthma, arthritis, inflammatory bowel disease, and cancer (5-7).In some systems, the proteinases that activate PARs have been established. For example, in the circulatory system, PAR 1 , PAR 3 , and PAR 4 are recognized physiological targets for thrombin (4), which does not efficiently acti...

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Targeting kallikrein 6‐proteolysis attenuates CNS inflammatory disease

Cited by 89 publications

References 49 publications

High Expression Rates of Human Islet Amyloid Polypeptide Induce Endoplasmic Reticulum Stress–Mediated β-Cell Apoptosis, a Characteristic of Humans With Type 2 but Not Type 1 Diabetes

High Expression Rates of Human Islet Amyloid Polypeptide Induce Endoplasmic Reticulum Stress–Mediated β-Cell Apoptosis, a Characteristic of Humans With Type 2 but Not Type 1 Diabetes

The Multiple Sclerosis Degradome: Enzymatic Cascades in Development and Progression of Central Nervous System Inflammatory Disease

Proteinase-activated Receptors, Targets for Kallikrein Signaling

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