• Antibody-drug conjugates
• Cathepsin B
• Cysteine cathepsin
• Nanoparticles
• Targeted therapy

• Apoptosis
• Cathepsin X
• Grouper
• Singapore grouper iridovirus

• Animals
• Fish Proteins/genetics
• Fish Proteins/metabolism
• Fish Diseases/immunology
• Fish Diseases/virology
• Cathepsins/metabolism
• Cathepsins/genetics
• Bass/immunology
• Bass/genetics
• Apoptosis
• Cloning, Molecular
• NF-kappa B/metabolism
• Humans
• Immunity, Innate
• Reoviridae Infections/immunology
• Reoviridae Infections/veterinary

• Autoimmune diseases
• Cancer therapy
• Cathepsins in immune cells
• Infectious diseases

• 81974469 and 81672635 The National Natural Science Foundation of China

• Anticancer therapy
• Cancer
• cysteine cathepsin
• diagnostic imaging
• protease
• targeted drug delivery

• Humans
• Neoplasms/drug therapy
• Neoplasms/enzymology
• Neoplasms/diagnosis
• Cathepsins/metabolism
• Cathepsins/antagonists & inhibitors
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/genetics
• Molecular Targeted Therapy
• Animals
• Apoptosis/drug effects
• Neovascularization, Pathologic/drug therapy

• genetics research
• cardiovascular genetics
• dna methylation

• Humans
• Bone Morphogenetic Proteins
• Cathepsin Z
• DNA Methylation/genetics
• Endothelial Cells
• Familial Primary Pulmonary Hypertension
• Pulmonary Arterial Hypertension

• MR/K020919/1 Medical Research Council
• SBF004\1095 Academy of Medical Sciences
• BDA number: 20/0006307 Diabetes UK
• Wellcome Trust
• FS/SBSRF/22/31025 British Heart Foundation
• British Heart Foundation (BHF)

• Alzheimer’s disease
• Huntington’s disease
• Parkinson’s disease
• amyotrophic lateral sclerosis
• cancer
• cathepsins
• lysosomal exopeptidases
• multiple sclerosis
• neurodegeneration
• neuropsychiatric disorders

• Humans
• Cysteine Proteases
• Neurodegenerative Diseases
• Cysteine/metabolism
• Cathepsin B
• Neoplasms
• Lysosomes/metabolism

• J1-2473, P1-0140 Slovenian Research Agency

• Adenocarcinoma/pathology
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Cathepsins
• Cross-Sectional Studies
• Female
• Gastric Mucosa/pathology
• Gastritis/pathology
• Helicobacter Infections/complications
• Helicobacter Infections/pathology
• Helicobacter pylori
• Humans
• Male
• Middle Aged
• Stomach Neoplasms/pathology
• Young Adult

Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults. Understanding GBM pathobiology and discovering novel therapeutic targets are critical to finding efficient treatments. Upregulation of the lysosomal cysteine carboxypeptidase cathepsin X has been linked to immune dysfunction and neurodegenerative diseases, but its role in cancer and particularly in GBM progression in patients is unknown. In this study, cathepsin X expression and activity were found to be upregulated in human GBM tissues compared to low-grade gliomas and nontumor brain tissues. Cathepsin X was localized in GBM cells as well as in tumor-associated macrophages and microglia. Subsequently, potent irreversible (AMS36) and reversible (Z7) selective cathepsin X inhibitors were tested in vitro. Selective cathepsin X inhibitors decreased the viability of patient-derived GBM cells as well as macrophages and microglia that were cultured in conditioned media of GBM cells. We next examined the expression pattern of neuron-specific enzyme γ-enolase, which is the target of cathepsin X. We found that there was a correlation between high proteolytic activity of cathepsin X and C-terminal cleavage of γ-enolase and that cathepsin X and γ-enolase were colocalized in GBM tissues, preferentially in GBM-associated macrophages and microglia. Taken together, our results on patient-derived material suggest that cathepsin X is involved in GBM progression and is a potential target for therapeutic approaches against GBM.

• cathepsin X
• cathepsin X inhibitors
• glioblastoma
• glioblastoma stem cells
• tumor microenvironment
• γ-enolase

• Brain Neoplasms/drug therapy
• Brain Neoplasms/genetics
• Brain Neoplasms/metabolism
• Cathepsin Z/antagonists & inhibitors
• Cathepsin Z/genetics
• Cathepsin Z/metabolism
• Gene Expression Regulation, Neoplastic
• Glioblastoma/drug therapy
• Glioblastoma/genetics
• Glioblastoma/metabolism
• Humans
• Macrophages/drug effects
• Macrophages/metabolism
• Microglia/drug effects
• Microglia/metabolism
• Phosphopyruvate Hydratase/metabolism
• Tumor Microenvironment
• Up-Regulation

• Cathepsins
• Extracellular matrix
• Gastric cancer
• Helicobacter pylori
• Inflammation

Cathepsin X is a lysosomal peptidase that is involved in tumour progression and represents a potential target for therapeutic interventions. In addition, it regulates important functions of immune cells and is implicated in the modulation of tumour cell–immune cell crosstalk. Selective cathepsin X inhibitors have been proposed as prospective antitumour agents to prevent cancer progression; however, their impact on the antitumour immune response has been overlooked. Previous studies indicate that the migration and adhesion of T cells and dendritic cells are affected by diminished cathepsin X activity. Meanwhile, the influence of cathepsin X inhibition on natural killer (NK) cell function has not yet been explored. Here, we examined the localization patterns of cathepsin X and the role of its inhibitors on the cytotoxicity of cell line NK-92, which is used for adoptive cellular immunotherapy in cancer patients. NK-92 cells depend on lymphocyte function-associated antigen 1 (LFA-1) to form stable immunoconjugates with target cells, providing, in this way, optimal cytotoxicity. Since LFA-1 is a substrate for cathepsin X activity in other types of cells, we hypothesized that cathepsin X could disturb the formation of NK-92 immunoconjugates. Thus, we employed cathepsin X reversible and irreversible inhibitors and evaluated their effects on the NK-92 cell interactions with target cells and on the NK-92 cell cytotoxicity. We show that cathepsin X inhibition does not impair stable conjugate formation or the lytic activity of NK-92 cells. Similarly, the conjugate formation between Jurkat T cells and target cells was not affected by cathepsin X activity. Unlike in previous migration and adhesion studies on T cells, in NK-92 cells cathepsin X was not co-localized with LFA-1 at the plasma membrane but was, rather, redistributed to the cytotoxic granules and secreted during degranulation.

• LFA-1
• NK-92
• cathepsin X
• cytotoxic cells
• immunological synapse

Macrophages are the first encounters of invading bacteria and are responsible for engulfing and digesting pathogens through phagocytosis leading to initiation of the innate inflammatory response. Intracellular digestion occurs through a close relationship between phagocytic/endocytic and lysosomal pathways, in which proteolytic enzymes, such as cathepsins, are involved. The presence of cathepsins in the endo-lysosomal compartment permits direct interaction with and killing of bacteria, and may contribute to processing of bacterial antigens for presentation, an event necessary for the induction of antibacterial adaptive immune response. Therefore, it is not surprising that bacteria can control the expression and proteolytic activity of cathepsins, including their inhibitors – cystatins, to favor their own intracellular survival in macrophages. In this review, we summarize recent developments in defining the role of cathepsins in bacteria-macrophage interaction and describe important strategies engaged by bacteria to manipulate cathepsin expression and activity in macrophages. Particularly, we focus on specific bacterial species due to their clinical relevance to humans and animal health, i.e., Mycobacterium, Mycoplasma, Staphylococcus, Streptococcus, Salmonella, Shigella, Francisella, Chlamydia, Listeria, Brucella, Helicobacter, Neisseria, and other genera.

• bacteria
• cathepsins
• immune invasion
• macrophages
• modulation of immune function

• Cathepsin X
• Cathepsin Z
• Homodimer
• Procathepsin X
• Protease
• Small-angle X-ray scattering

• cathepsins
• human leukocyte antigen
• leukemia
• neoplasm

Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases.

• cathepsins
• lysosomal storage diseases
• mucopolysaccharidoses
• therapy

• Cathepsins/antagonists & inhibitors
• Cathepsins/deficiency
• Cathepsins/genetics
• Cathepsins/metabolism
• Humans
• Models, Biological
• Mucopolysaccharidoses/enzymology
• Mucopolysaccharidoses/physiopathology
• Mucopolysaccharidoses/therapy
• Mutation/genetics
• Protease Inhibitors/therapeutic use

• Cathepsin Z
• Edwardsiella piscicida
• Pagrus major
• Red sea bream iridovirus (RSIV)
• Streptococcus iniae

• Amino Acid Sequence
• Animals
• Cathepsin Z/chemistry
• Cathepsin Z/genetics
• Cathepsin Z/immunology
• DNA Virus Infections/immunology
• DNA Virus Infections/veterinary
• Edwardsiella/physiology
• Enterobacteriaceae Infections/immunology
• Enterobacteriaceae Infections/veterinary
• Fish Diseases/immunology
• Fish Proteins/chemistry
• Fish Proteins/genetics
• Fish Proteins/immunology
• Gene Expression Profiling/veterinary
• Gene Expression Regulation/immunology
• Immunity, Innate/genetics
• Iridoviridae/physiology
• Phylogeny
• Sea Bream/genetics
• Sea Bream/immunology
• Sequence Alignment/veterinary
• Streptococcal Infections/immunology
• Streptococcal Infections/veterinary
• Streptococcus iniae/physiology

• cancer progression
• cysteine cathepsins
• drug resistance

• Animals
• Antineoplastic Agents/therapeutic use
• Cathepsins/chemistry
• Cathepsins/classification
• Cathepsins/genetics
• Cathepsins/metabolism
• Cell Death/drug effects
• Cell Death/genetics
• Cell Line, Tumor
• Drug Resistance, Neoplasm/genetics
• Extracellular Matrix/drug effects
• Extracellular Matrix/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Lymphatic Metastasis
• Lysosomes/drug effects
• Lysosomes/enzymology
• Models, Molecular
• Neoplasms/drug therapy
• Neoplasms/enzymology
• Neoplasms/genetics
• Neoplasms/pathology
• Neovascularization, Pathologic/drug therapy
• Neovascularization, Pathologic/enzymology
• Neovascularization, Pathologic/genetics
• Neovascularization, Pathologic/pathology
• Protein Conformation
• Proto-Oncogene Proteins c-bcl-2/genetics
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Signal Transduction

• 16-15-10410 Russian Science Foundation

• Angiogenesis
• Cancer
• Cathepsins
• Metastasis: Drug resistance: Inhibitors

Glioblastoma is a highly aggressive central nervous system neoplasm characterized by extensive infiltration of malignant cells into brain parenchyma, thus preventing complete tumor eradication. Cysteine cathepsins B, S, L and K are involved in cancer progression and are overexpressed in glioblastoma. We report here for the first time that cathepsin X mRNA and protein are also abundantly present in malignant glioma.

Gene expression of cathepsins K and X was analyzed using publically-available tran-scriptomic datasets and correlated with glioma grade and glioblastoma subtype. Kaplan-Maier survival analysis was performed to evaluate the predictive value of cathepsin K and X mRNA expression. Cathepsin protein expression was localized and semi-quantified in tumor tissues by immunohistochemistry.

Highest gene expression of cathepsins K and X was found in glioblastoma, in particular in the mesenchymal subtype. Overall, high mRNA expression of cathepsin X, but not that of cathepsin K, correlated with poor patients’ survival. Cathepsin K and X proteins were abundantly and heterogeneously expressed in glioblastoma tissue. Immuno-labeling of cathepsins K and X was observed in areas of CD133-positive glioblastoma stem cells, localized around arterioles in their niches that also expressed SDF-1α and CD68. mRNA levels of both cathepsins K and X correlated with mRNA levels of markers of glioblastoma stem cells and their niches.

The presence of both cathepsins in glioblastoma stem cell niche regions indicates their possible role in regulation of glioblastoma stem cell homing in their niches. The clinical relevance of this data needs to be elaborated in further prospective studies.

• cancer stem cell niches
• cathepsins
• glioblastoma
• immunohistochemistry
• patient survival

Our recent genome-wide association study found that the NELFCD/CTSZ locus was significantly associated with progression of primary biliary cholangitis (PBC) to jaundice stage in the Japanese population. In this study, we investigated the role of cathepsin Z in the etiology and pathology of PBC. Serum cathepsin Z levels were measured using enzyme-linked immunosorbent assay. The expression and localization of cathepsin Z in liver specimens were analyzed by western blotting and immunohistochemistry. In PBC patients, serum cathepsin Z levels were significantly increased with disease progression. In addition, its levels were positively correlated with alanine transaminase, aspartate transaminase and total bilirubin, and were negatively correlated with platelet count and albumin. Cathepsin Z expression was markedly increased in hepatocytes at later stages of PBC, and its localization was altered from the peri-bile canaliculus to the cytoplasm, where a fraction was no longer colocalized with endosomal/lysosomal vesicles. Similar altered expression of cathepsin Z was observed in end-stage of other cholestatic liver diseases including sepsis, obstructive jaundice, and Alagille syndrome. Our results indicate that altered expression and localization of cathepsin Z in hepatocytes are characteristic features of PBC and other cholestatic liver diseases, and are implicated in the progression of PBC.

• CtsZ
• Deguelin
• FAK/Src/Paxillin signaling
• Metastasis
• NSCLC

• A549 Cells
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Cathepsin Z/genetics
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Movement/genetics
• Focal Adhesion Kinase 1/genetics
• Gene Expression Regulation, Neoplastic/drug effects
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Neoplasm Metastasis/drug therapy
• Neoplasm Metastasis/genetics
• Rotenone/analogs & derivatives
• Rotenone/pharmacology
• Signal Transduction/drug effects
• Signal Transduction/genetics

• Anticancer therapies
• Cathepsins
• Cystatins
• Cysteine cathepsins
• Inhibitors

Cathepsins are lysosomal peptidases belonging to the papain family, and based on their catalytic sites, these enzymes can be divided into serine, cysteine and aspartic proteases. The studies conducted to date have identified, 15 types of cathepsins that are widely distributed in intracellular and extracellular spaces. These proteases participate in various pathological activities, including the occurrence and development of human cancers. Several recent studies suggest that cathepsins, particularly cathepsins B, D, E and L, contribute to digestive tumorigenesis. Cathepsins were found to promote the development of most digestive cancers except liver cancer, in which they might have the opposite effects. Due to their important roles in digestive tumors, cathepsins might be therapeutic targets for the treatment of digestive cancers.

• cathepsin
• digestive cancer
• invasion
• migration
• proliferation

Recent studies underscore the role of the microenvironment in therapy resistance of chronic myeloid leukemia (CML) cells and leukemia progression. We previously showed that sustained mild activation of endoplasmic reticulum (ER) stress in CML cells supports their survival and resistance to chemotherapy. We now demonstrate, using dominant negative non-phosphorylable mutant of eukaryotic initiation factor 2 α subunit (eIF2α), that phosphorylation of eIF2α (eIF2α-P), which is a hallmark of ER stress in CML cells, substantially enhances their invasive potential and modifies their ability to secrete extracellular components, including the matrix-modifying enzymes cathepsins and matrix metalloproteinases. These changes are dependent on the induction of activating transcription factor-4 (ATF4) and facilitate extracellular matrix degradation by CML cells. Conditioned media from CML cells with constitutive activation of the eIF2α-P/ATF4 pathway induces invasiveness of bone marrow stromal fibroblasts, suggesting that eIF2α-P may be important for extracellular matrix remodeling and thus leukemia cells-stroma interactions. Our data show that activation of stress response in CML cells may contribute to the disruption of bone marrow niche components by cancer cells and in this way support CML progression.

• ATF4
• CML
• cell invasion
• eIF2α
• proteases

Cathepsins are proteolytic enzymes with a broad spectrum of substrates. They are known to reside within endo-lysosomes where they acquire optimal conditions for proteolytic activity and substrate cleavage. However, cathepsins have been detected in locations other than the canonical compartments of the endocytotic pathway. They are often secreted from cells in either proteolytically inactive proform or as mature and active enzyme; this may happen in both physiological and pathological conditions. Moreover, cytosolic and nuclear forms of cathepsins have been described and are currently an emerging field of research aiming at understanding their functions in such unexpected cellular locations. This chapter summarizes the canonical pathways of biosynthesis and transport of cathepsins in healthy cells. We further describe how cathepsins can reach unexpected locations such as the extracellular space or the cytosol and the nuclear matrix. No matter where viruses and cathepsins encounter, several outcomes can be perceived. Thus, scenarios are discussed on how cathepsins may support virus entry into host cells, involve in viral fusion factor and polyprotein processing in different host cell compartments, or help in packaging of viral particles during maturation. It is of note to mention that this review is not meant to comprehensively cover the present literature on viruses encountering cathepsins but rather illustrates, on some representative examples, the possible roles of cathepsins in replication of viruses and in the course of disease.

Kidney disease is worldwide the 12th leading cause of death affecting 8–16% of the entire population. Kidney disease encompasses acute (short-lasting episode) and chronic (developing over years) pathologies both leading to renal failure. Since specific treatments for acute or chronic kidney disease are limited, more than 2 million people a year require dialysis or kidney transplantation. Several recent evidences identified lysosomal proteases cathepsins as key players in kidney pathophysiology. Cathepsins, originally found in the lysosomes, exert important functions also in the cytosol and nucleus of cells as well as in the extracellular space, thus participating in a wide range of physiological and pathological processes. Based on their catalytic active site residue, the 15 human cathepsins identified up to now are classified in three different families: serine (cathepsins A and G), aspartate (cathepsins D and E), or cysteine (cathepsins B, C, F, H, K, L, O, S, V, X, and W) proteases. Specifically in the kidney, cathepsins B, D, L and S have been shown to regulate extracellular matrix homeostasis, autophagy, apoptosis, glomerular permeability, endothelial function, and inflammation. Dysregulation of their expression/activity has been associated to the onset and progression of kidney disease. This review summarizes most of the recent findings that highlight the critical role of cathepsins in kidney disease development and progression. A better understanding of the signaling pathways governed by cathepsins in kidney physiopathology may yield novel selective biomarkers or therapeutic targets for developing specific treatments against kidney disease.

• acute kidney injury
• cathepsins
• chronic kidney disease
• lysosomal proteases
• signaling pathways

Helicobacter pylori (H. pylori) infection has often no clinical signs and is one of the most common bacterial infections. All infected subjects have histology of active chronic gastritis. In some cases patients develop peptic ulcer and minority of them develop gastric cancer. Gastric cancer is multifactorial disease, thus various progressions of H. pylori infection and disease are dependent on the host genetic factors, the characteristics of the individual’s immune response, environmental factors, and different bacterial virulence factors of the individual bacterial strains. Eradication of the bacteria plays a crucial role in the treatment of these cases however antibiotic therapy does not always help. Bacteria often develop resistance to antibiotics so we recommend that not only screening for H. pylori also the strain determination should have some diagnostic value, especially in the patients who already developed gastritis. Furthermore, for such patients assessment of disease progression (atrophic or metaplastic gastritis) could be followed by polymorphism determination. Until now we cannot predict the disease based only on single polymorphism. Bacteria successfully neutralize the responses of the immune systems using different enzymes or even components of the host immune response. However, the influence of immune system and its components could represent new ways of treatments and could help to eradicate the infection.

• Helicobacter pylori
• Resistance to antibiotics
• Immune response
• Genetic factors
• Bacterial eradication

• 20-Ecdysone
• Cathepsin O
• Infection
• Molecular cloning
• Silkworm

Epithelial-to-mesenchymal transition (EMT) represents conversion of an epithelial cell in an elongated cell with mesenchymal phenotype, which can occur in physiologic and pathologic processes such as embryogenesis (type 1 EMT), wound healing and/or fibrosis (type 2 EMT) and malignant tumors (type 3 EMT). The proliferation rate, metastasizing and recurrence capacity, as also the individualized response at chemotherapics, in both epithelial and mesenchymal malignant tumors is known to be influenced by reversible switch between EMT and mesenchymal-to-epithelial transition (MET). Although much research work has already been done in these fields, the specific molecular pathways of EMT, relating to the tumor type and tumor localization, are yet to be elucidated. In this paper, based on the literature and personal experience of the authors, an update in the field of EMT vs MET in epithelial and mesenchymal tumors is presented. The authors tried to present the latest data about the particularities of these processes, and also of the so-called endothelial-to-mesenchymal transition, based on tumor location. The EMT-angiogenesis link is discussed as a possible valuable parameter for clinical follow-up and targeted therapeutic oncologic management. The paper begins with presentation of the basic aspects of EMT, its classification and assessment possibilities, and concludes with prognostic and therapeutic perspectives. The particularities of EMT and MET in gastric and colorectal carcinomas, pancreatic cancer, hepatocellular and cholangiocarcinomas, and lung, breast and prostate cancers, respectively in sarcomas and gastrointestinal stromal tumors are presented in detail.

• Gastrointestinal stromal tumor
• Carcinoma
• Gastrointestinal cancer
• Hepatic cancer
• Sarcoma

• cell invasion
• cell migration
• protease
• tumor microenvironment

• Apoptosis
• Cathepsin X
• Gastric cancer
• Ribosomal phosphoprotein P0 (RPLP0)
• Yeast two-hybrid

• Cathepsin X
• Coculture
• Colorectal cancer

• cathepsin
• inflammation
• lysosomal proteinase
• macrophage
• reflux esophagitis

The immune response to Helicobacter pylori importantly determines the pathogenesis of infection as well as the success of antibiotic eradication of the bacteria. Strains of H. pylori were gathered from 14 patients who failed to eradicate H. pylori infection with antibiotics—therapy resistant strains (TRS)—or from patients who were able to eradicate H. pylori infection—therapy susceptible strains (TSS). The THP-1 cells were stimulated with H. pylori antigens. Cathepsin X expression on THP-1 cells and concentration of cytokines in the supernatant of THP-1 cells were measured with a flow cytometer. TSS H. pylori antigens increased the proportion of cathepsin X positive cells compared to TRS H. pylori antigens. TSS H. pylori antigens induced higher secretion of IL-12 and IL-6 compared to TRS H. pylori antigens (P < 0.001; 0.02). Polymyxin B, a lipid A inhibitor, lowered the secretion of IL-12 and IL-6 in TRS and TSS. We demonstrated a H. pylori strain-dependent cathepsin X and cytokine expression that can be associated with H. pylori resistance to eradication due to lack of effective immune response. Differences in lipid A of H. pylori might have an influence on the insufficient immune response, especially on phagocytosis.

• Helicobacter pylori
• Innate immune response
• antimicrobial response
• cathepsin X
• cytokines
• polymyxin B

The immune response to Helicobacter pylori importantly determines the outcome of infection as well as the success of eradication therapy. We demonstrate the role of a cysteine protease cathepsin X in the immune response to H. pylori infection.

We analysed how the inhibition of cathepsin X influenced the immune response in experiments when THP-1 cells or dendritic cells isolated from patients were stimulated with 48 strains of H. pylori isolated from gastric biopsy samples of patients which had problems with the eradication of bacteria.

The experiments, performed with the help of a flow cytometer, showed that the expression of Toll-like receptors (TLRs), especially TLR-4 molecules, on the membranes of THP-1 cells or dendritic cells was higher when we stimulated cells with H. pylori together with inhibitor of cathepsin X 2F12 compared to THP-1 cells or dendritic cells stimulated with H. pylori only, and also in comparison with negative control samples. We also demonstrated that when we inhibited the action of cathepsin X in THP-1 cells, the concentrations of pro-inflammatory cytokines were lower than when THP-1 cell were stimulated with H. pylori only.

We demonstrated that inhibition of cathepsin X influences the internalization of TLR-2 and TLR-4. TLR-2 and TLR-4 redistribution to intra-cytoplasmic compartments is hampered if cathepsin X is blocked. The beginning of a successful immune response against H. pylori in the case of inhibition of cathepsin X is delayed.

• cathepsin X
• cytokines
• dendritic cells
• hampered immune response
• macrophages
• toll-like receptors

Helicobacter pylori are responsible for the induction of chronic gastric inflammation progressing to atrophy, metaplasia, and gastric cancer. The overexpression of Cathepsin X/Z (Ctsz) in H. pylori-infected mucosa and gastric cancer is mediated predominantly by an augmented migration of ctsz^−/−positive macrophages and the up-regulation of Ctsz in tumor epithelium. To explore the Ctsz-function in the context of chronic inflammation and the development of preneoplastic lesions, we used Ctsz-deficient mice in a H. pylori gastritis model. Ctsz^−/− and wild-type (wt) mice were infected with H. pylori strain SS1. The mice were sacrificed at 24, 36, and 50 weeks post infection (wpi). The stomach was removed, and gastric strips were snap-frozen or embedded and stained with H&E. Tissue sections were scored for epithelial lesions and inflammation. Ki-67 and F4/80 immunostaining were used to measure epithelial cell proliferation and macrophage infiltration, respectively. The upregulation of compensating cathepsins and cytokines were confirmed by Western blotting and quantitative RT-PCR. SS1-infected wt and ctsz^−/− mice showed strong inflammation, foveolar hyperplasia, atrophy, and cystically-dilated glands. However, at 50 wpi, ctsz^−/− mice developed significantly more severe spasmolytic polypeptide-expressing metaplasia (SPEM), showed enhanced epithelial proliferation, and higher levels of infiltrating macrophages. Induction of cytokines was higher and significantly prolonged in ctsz^−/− mice compared to wt. Ctsz deficiency supports H. pylori-dependent development of chronic gastritis up to metaplasia, indicating a protective, but not proteolytic, function of Ctsz in inflammatory gastric disease.

• Animals
• Cathepsin B/genetics
• Cathepsin B/metabolism
• Cathepsin Z/deficiency
• Cathepsin Z/genetics
• Cathepsin Z/metabolism
• Cytokines/metabolism
• Dilatation, Pathologic
• Disease Models, Animal
• Gastric Mucosa/metabolism
• Gastric Mucosa/pathology
• Gene Expression
• Helicobacter Infections/genetics
• Helicobacter pylori
• Hyperplasia
• Inflammation Mediators/metabolism
• Mice
• Mice, Knockout
• Precancerous Conditions/genetics
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology