Browsing by Subject "GENE-EXPRESSION"

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  • Verbeeren, Jens; Verma, Bhupendra; Niemela, Elina H.; Yap, Karen; Makeyev, Eugene V.; Frilander, Mikko J. (2017)
    Cellular homeostasis of the minor spliceosome is regulated by a negative feed-back loop that targets U11-48K and U11/U12-65K mRNAs encoding essential components of the U12-type intron-specific U11/U12 di-snRNP. This involves interaction of the U11 snRNP with an evolutionarily conserved splicing enhancer giving rise to unproductive mRNA isoforms. In the case of U11/U12-65K, this mechanism controls the length of the 3' untranslated region (3'UTR). We show that this process is dynamically regulated in developing neurons and some other cell types, and involves a binary switch between translation-competent mRNAs with a short 3'UTR to non-productive isoforms with a long 3'UTR that are retained in the nucleus or/and spliced to the downstream amylase locus. Importantly, the choice between these alternatives is determined by alternative terminal exon definition events regulated by conserved U12-and U2-type 50 splice sites as well as sequence signals used for pre-mRNA cleavage and polyadenylation. We additionally show that U11 snRNP binding to the U11/U12-65K mRNA species with a long 3'UTR is required for their nuclear retention. Together, our studies uncover an intricate molecular circuitry regulating the abundance of a key spliceosomal protein and shed new light on the mechanisms limiting the export of non-productively spliced mRNAs from the nucleus to the cytoplasm.
  • Singh, Abhishek A.; Mandoli, Amit; Prange, Koen H. M.; Laakso, Marko; Martens, Joost H. A. (2017)
    Chromosomal translocations are one of the hallmarks of acute myeloid leukemia (AML), often leading to gene fusions and expression of an oncofusion protein. Over recent years it has become clear that most of the AML associated oncofusion proteins molecularly adopt distinct mechanisms for inducing leukemogenesis. Still these unique molecular properties of the chimeric proteins converge and give rise to a common pathogenic molecular mechanism. In the present study we compared genome-wide DNA binding and transcriptome data associated with AML1-ETO, CBFB-MYH11 and PML-RARA oncofusion protein expression to identify unique and common features. Our analyses revealed targeting of oncofusion binding sites to RUNX1 and ETS-factor occupied genomic regions. In addition, it revealed a highly comparable global histone acetylation pattern, similar expression of common target genes and related enrichment of several biological pathways critical for maintenance of AML, suggesting oncofusion proteins deregulate common gene programs despite their distinct binding signatures and mechanisms of action.
  • Inouye, Michael; Silander, Kaisa; Hämäläinen, Eija; Salomaa, Veikko; Harald, Kennet; Jousilahti, Pekka; Mannisto, Satu; Eriksson, Johan G.; Saarela, Janna; Ripatti, Samuli; Perola, Markus; van Ommen, Gert-Jan B.; Taskinen, Marja-Riitta; Palotie, Aarno; Dermitzakis, Emmanouil T.; Peltonen, Leena (2010)
  • Wang, Xin; Ye, Lingling; Lyu, Munan; Ursache, Robertas; Löytynoja, Ari; Mähönen, Ari Pekka (2020)
    Conditional manipulation of gene expression is a key approach to investigating the primary function of a gene in a biological process. While conditional and cell-type-specific overexpression systems exist for plants, there are currently no systems available to disable a gene completely and conditionally. Here, we present a new tool with which target genes can efficiently and conditionally be knocked out by genome editing at any developmental stage. Target genes can also be knocked out in a cell-type-specific manner. Our tool is easy to construct and will be particularly useful for studying genes having null alleles that are non-viable or show pleiotropic developmental defects.
  • Mozhgani, Sayed-Hamidreza; Piran, Mehran; Zarei-Ghobadi, Mohadeseh; Jafari, Mohieddin; Jazayeri, Seyed-Mohammad; Mokhtari-Azad, Talat; Teymoori-Rad, Majid; Valizadeh, Narges; Farajifard, Hamid; Mirzaie, Mehdi; Khamseh, Azam; Rafatpanah, Houshang; Rezaee, Seyed-Abdolrahim; Norouzi, Mehdi (2019)
    Background Human T-lymphotropic virus 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive disease of the central nervous system that significantly affected spinal cord, nevertheless, the pathogenesis pathway and reliable biomarkers have not been well determined. This study aimed to employ high throughput meta-analysis to find major genes that are possibly involved in the pathogenesis of HAM/TSP. Results High-throughput statistical analyses identified 832, 49, and 22 differentially expressed genes for normal vs. ACs, normal vs. HAM/TSP, and ACs vs. HAM/TSP groups, respectively. The protein-protein interactions between DEGs were identified in STRING and further network analyses highlighted 24 and 6 hub genes for normal vs. HAM/TSP and ACs vs. HAM/TSP groups, respectively. Moreover, four biologically meaningful modules including 251 genes were identified for normal vs. ACs. Biological network analyses indicated the involvement of hub genes in many vital pathways like JAK-STAT signaling pathway, interferon, Interleukins, and immune pathways in the normal vs. HAM/TSP group and Metabolism of RNA, Viral mRNA Translation, Human T cell leukemia virus 1 infection, and Cell cycle in the normal vs. ACs group. Moreover, three major genes including STAT1, TAP1, and PSMB8 were identified by network analysis. Real-time PCR revealed the meaningful down-regulation of STAT1 in HAM/TSP samples than AC and normal samples (P = 0.01 and P = 0.02, respectively), up-regulation of PSMB8 in HAM/TSP samples than AC and normal samples (P = 0.04 and P = 0.01, respectively), and down-regulation of TAP1 in HAM/TSP samples than those in AC and normal samples (P = 0.008 and P = 0.02, respectively). No significant difference was found among three groups in terms of the percentage of T helper and cytotoxic T lymphocytes (P = 0.55 and P = 0.12). Conclusions High-throughput data integration disclosed novel hub genes involved in important pathways in virus infection and immune systems. The comprehensive studies are needed to improve our knowledge about the pathogenesis pathways and also biomarkers of complex diseases.
  • Serra, Angela; Önlü, Serli; Coretto, Pietro; Greco, Dario (2019)
    Traditional quantitative structure-activity relationship models usually neglect the molecular alterations happening in the exposed systems (the mechanism of action, MOA), that mediate between structural properties of compounds and phenotypic effects of an exposure.
  • Kibble, Milla; Khan, Suleiman A.; Ammad-ud-din, Muhammad; Bollepalli, Sailalitha; Palviainen, Teemu; Kaprio, Jaakko; Pietiläinen, Kirsi H.; Ollikainen, Miina (2020)
    We combined clinical, cytokine, genomic, methylation and dietary data from 43 young adult monozygotic twin pairs (aged 22-36 years, 53% female), where 25 of the twin pairs were substantially weight discordant (delta body mass index > 3 kg m(-2)). These measurements were originally taken as part of the TwinFat study, a substudy of The Finnish Twin Cohort study. These five large multivariate datasets (comprising 42, 71, 1587, 1605 and 63 variables, respectively) were jointly analysed using an integrative machine learning method called group factor analysis (GFA) to offer new hypotheses into the multi-molecular-level interactions associated with the development of obesity. New potential links between cytokines and weight gain are identified, as well as associations between dietary, inflammatory and epigenetic factors. This encouraging case study aims to enthuse the research community to boldly attempt new machine learning approaches which have the potential to yield novel and unintuitive hypotheses. The source code of the GFA method is publically available as the R package GFA.
  • Hamari, S.; Kirveskoski, T.; Glumoff, V.; Kulmala, P.; Simell, O.; Knip, M.; Veijola, R. (2016)
    Our aim was to study whether the aberrant amount or function of regulatory T cells is related to the development of type 1 diabetes (T1D) in children. We also set out to investigate the balance of different T cell subtype markers during the T1D autoimmune process. Treg cells were quantified with flow cytometric assay, and the suppression capacity was analysed with a carboxyfluorescein succinimidyl ester (CFSE)-based T cell suppression assay in children in various phases of T1D disease process and in healthy autoantibody-negative control children. The mRNA expression of different T cell subpopulation markers was analysed with real-time qPCR method. The proportion and suppression capacity of regulatory T cells were similar in seroconverted children at an early stage of beta cell autoimmunity and also in children with T1D when compared to healthy and autoantibody-negative children. Significant differences were observed in the mRNA expression of different T cell subpopulation markers in prediabetic children with multiple (2) autoantibodies and in children with newly diagnosed T1D when compared to the control children. In conclusion, there were no quantitative or functional differences in regulatory T cells between the case and control groups in any phase of the autoimmune process. Decreased mRNA expression levels of T cell subtype markers were observed in children with multiple islet autoantibodies and in those with newly diagnosed T1D, probably reflecting an exhaustion of the immune system after the strong immune activation during the autoimmune process or a generally aberrant immune response related to the progression of the disease.
  • Knuuttila, Matias; Mehmood, Arfa; Huhtaniemi, Riikka; Yatkin, Emrah; Häkkinen, Merja R.; Oksala, Riikka; Laajala, Teemu D.; Ryberg, Henrik; Handelsman, David J.; Aittokallio, Tero; Auriola, Seppo; Ohlsson, Claes; Laiho, Asta; Elo, Laura L.; Sipila, Petra; Makela, Sari I.; Poutanen, Matti (2018)
    The development of castration-resistant prostate cancer (CRPC) is associated with the activation of intratumoral androgen biosynthesis and an increase in androgen receptor (AR) expression. We recently demonstrated that, similarly to the clinical CRPC, orthotopically grown castration-resistant VCaP (CR-VCaP) xenografts express high levels of AR and retain intratumoral androgen concentrations similar to tumors grown in intact mice. Herein, we show that antiandrogen treatment (enzalutamide or ARN-509) significantly reduced (10-fold, P <0.01) intratumoral testosterone and dihydrotestosterone concentrations in the CR-VCaP tumors, indicating that the reduction in intratumoral androgens is a novel mechanism by which antiandrogens mediate their effects in CRPC. Antiandrogen treatment also altered the expression of multiple enzymes potentially involved in steroid metabolism. Identical to clinical CRPC, the expression levels of the full-length AR (twofold, P <0.05) and the AR splice variants 1 (threefold, P <0.05) and 7 (threefold, P <0.01) were further increased in the antiandrogen-treated tumors. Nonsignificant effects were observed in the expression of certain classic androgen-regulated genes, such as TMPRSS2 and KLK3, despite the low levels of testosterone and dihydrotestosterone. However, other genes recently identified to be highly sensitive to androgen-regulated AR action, such as NOV and ST6GalNAc1, were markedly altered, which indicated reduced androgen action. Taken together, the data indicate that, besides blocking AR, antiandrogens modify androgen signaling in CR-VCaP xenografts at multiple levels.
  • Kale, Liga; Nakurte, Ilva; Jalakas, Pirko; Kunga-Jegere, Laura; Brosche, Mikael; Rostoks, Nils (2019)
    Arabidopsis thaliana cyclic nucleotide-gated ion channel gene 4 (AtCNGC4) loss-of-function mutant dnd2 exhibits elevated accumulation of salicylic acid (SA), dwarfed morphology, reduced hypersensitive response (HR), altered disease resistance and spontaneous lesions on plant leaves. An orthologous barley mutant, nec1, has been reported to over-accumulate indole-3-acetic acid (IAA) and to exhibit changes in stomatal regulation in response to exogenous auxin. Here we show that the Arabidopsis dnd2 over-accumulates both IAA and abscisic acid (ABA) and displays related phenotypic and physiological changes, such as, reduced stomatal size, higher stomatal density and stomatal index. dnd2 showed increased salt tolerance in root growth assay and significantly reduced stomatal conductance, while maintaining near wt reaction in stomatal conductance upon external application of ABA, and probably consequently increased drought stress tolerance. Introduction of both sid2-1 and fmo1 into dnd2 background resulting in removal of SA did not alter stomatal conductance. Hence, the closed stomata of dnd2 is probably a result of increased ABA levels and not increased SA levels. The triple dnd2sid2abi1-1 mutant exhibited intermediate stomatal conductance compared to dnd2 and abil-1 (ABA insensitive, open stomata), while the response to external ABA was as in abi1-1 suggesting that reduced stomatal conductance in dnd2 is not due to impaired ABA signaling. In conclusion, Arabidopsis dnd2 mutant exhibited ABA overaccumulation and stomatal phenotypes, which may contribute to the observed improvement in drought stress resistance. Thus, Arabidopsis dnd2 mutant may serve as a model for studying crosstalk between biotic and abiotic stress and hormonal response in plants.
  • Österlund, Pamela; Jiang, Miao; Westenius, Veera; Kuivanen, Suvi; Järvi, Riia; Kakkola, Laura; Lundberg, Rickard; Melen, Krister; Korva, Misa; Avsic-Zupanc, Tatjana; Vapalahti, Olli; Julkunen, Ilkka (2019)
    Zika virus (ZIKV) infections in humans are considered to be mild or subclinical. However, during the recent epidemics in the Pacific Islands and the Americas, the infection was associated with Quillain-Barre syndrome and congenital infections with fetal brain abnormalities, including microcephaly. Thus, more detailed understanding of ZIKV-host cell interactions and regulation of innate immune responses by strains of differential evolutionary origin is required. Here, we characterized the infection and immune responses triggered by two epidemic Asian/American lineage viruses, including an isolate from fetal brains, and a historical, low passage 1947 African lineage virus in human monocyte-derived dendritic cells (DCs) and macrophages. The epidemic Asian/American ZIKV replicated well and induced relatively good antiviral responses in human DCs whereas the African strain replicated less efficiently and induced weaker immune responses. In macrophages both the African and Asian strains showed limited replication and relatively weak cytokine gene expression. Interestingly, in macrophages we observed host protein degradation, especially IRF3 and STAT2, at early phases of infection with both lineage viruses, suggesting an early proteasomal activation in phagocytic cells. Our data indicates that ZIKV evolution has led to significant phenotypic differences in the replication characteristics leading to differential regulation of host innate immune responses.
  • Biswal, Ajaya K.; Soeno, Kazuo; Gandla, Madhavi Latha; Immerzeel, Peter; Pattathil, Sivakumar; Lucenius, Jessica; Serimaa, Ritva; Hahn, Michael G.; Moritz, Thomas; Jonsson, Leif J.; Israelsson-Nordstrom, Maria; Mellerowicz, Ewa J. (2014)
  • Gupta, Rashi; Greco, Dario; Auvinen, Petri; Arjas, Elja (2010)
  • Jokinen, T. S.; Tiira, K.; Metsähonkala, L.; Seppala, E. H.; Hielm-Bjorkman, A.; Lohi, H.; Laitinen-Vapaavuori, O. (2015)
    BackgroundLagotto Romagnolo (LR) dogs with benign juvenile epilepsy syndrome often experience spontaneous remission of seizures. The long-term outcome in these dogs currently is unknown. In humans, behavioral and psychiatric comorbidities have been reported in pediatric and adult-onset epilepsies. Hypothesis/ObjectivesThe objectives of this study were to investigate possible neurobehavioral comorbidities in LR with a history of benign familial juvenile epilepsy (BFJE) and to assess the occurrence of seizures after the remission of seizures in puppyhood. AnimalsA total of 25 LR with a history of BFJE and 91 control dogs of the same breed. MethodsOwners of the LR dogs in the BFJE and control groups completed an online questionnaire about each dog's activity, impulsivity, and inattention. Principal component analysis (PCA) served to extract behavioral factors from the data. We then compared the scores of these factors between the 2 groups in a retrospective case-control study. We also interviewed all dog owners in the BFJE group by telephone to inquire specifically about possible seizures or other neurological problems after remission of seizures as a puppy. ResultsLagotto Romagnolo dogs with BFJE showed significantly higher scores on the factors Inattention and Excitability/Impulsivity than did the control group (P=.003; P=.021, respectively). Only 1 of the 25 BFJE LR exhibited seizures after remission of epilepsy in puppyhood. Conclusions and Clinical ImportanceAlthough the long-term seizure outcome in BFJE LR seems to be good, the dogs exhibit behavioral abnormalities resembling attention deficit hyperactivity disorder (ADHD) in humans, thus suggesting neurobehavioral comorbidities with epilepsy.
  • Czamara, Darina; Dieckmann, Linda; Roeh, Simone; Kraemer, Sarah; Rancourt, Rebecca C.; Sammallahti, Sara; Kajantie, Eero; Laivuori, Hannele; Eriksson, Johan G.; Räikkönen, Katri; Henrich, Wolfgang; Plagemann, Andreas; Binder, Elisabeth B.; Braun, Thorsten; Entringer, Sonja (2021)
    Background Glucocorticoids (GCs) play a pivotal role in fetal programming. Antenatal treatment with synthetic GCs (sGCs) in individuals in danger of preterm labor is common practice. Adverse short- and long-term effects of antenatal sGCs have been reported, but their effects on placental epigenetic characteristics have never been systematically studied in humans. Results We tested the association between exposure to the sGC betamethasone (BET) and placental DNA methylation (DNAm) in 52 exposed cases and 84 gestational-age-matched controls. We fine-mapped associated loci using targeted bisulfite sequencing. The association of placental DNAm with gene expression and co-expression analysis on implicated genes was performed in an independent cohort including 494 placentas. Exposure to BET was significantly associated with lower placenta DNAm at an enhancer of FKBP5. FKBP5 (FK506-binding protein 51) is a co-chaperone that modulates glucocorticoid receptor activity. Lower DNAm at this enhancer site was associated with higher expression of FKBP5 and a co-expressed gene module. This module is enriched for genes associated with preeclampsia and involved in inflammation and immune response. Conclusions Our findings suggest that BET exposure during pregnancy associates with few but lasting changes in placental DNAm and may promote a gene expression profile associated with placental dysfunction and increased inflammation. This may represent a pathway mediating GC-associated negative long-term consequences and health outcomes in offspring.
  • Claassens, Nico J.; Finger-Bou, Max; Scholten, Bart; Muis, Frederieke; de Groot, Jonas J.; de Gier, Jan-Willem; de Vos, Willem M.; van der Oost, John (2019)
    Escherichia coli has been widely used as a platform microorganism for both membrane protein production and cell factory engineering. The current methods to produce membrane proteins in this organism require the induction of target gene expression and often result in unstable, low yields. Here, we present a method combining a constitutive promoter with a library of bicistronic design (BCD) elements, which enables inducer-free, tuned translation initiation for optimal protein production. Our system mediates stable, constitutive production of bacterial membrane proteins at yields that outperform those obtained with E. coli Lemo21(DE3), the current gold standard for bacterial membrane protein production. We envisage that the continuous, fine-tunable, and high-level production of membrane proteins by our method will greatly facilitate their study and their utilization in engineering cell factories.
  • Virtanen, Elina; Seppälä, Hanna; Helanterä, Ilkka; Laine, Pia; Lautenschlager, Irmeli; Paulin, Lars; Mannonen, Laura; Auvinen, Petri; Auvinen, Eeva (2018)
    Background: BK polyomavirus (BKPyV) infection is a common asymptomatic viral infection in the general population. Severe complications are seen in immunocompromised individuals, such as polyomavirus-associated nephropathy (PyVAN) in renal transplant recipients. Information on BKPyV microRNA expressions is scarce, although polyomavirus-encoded microRNAs have been shown to control viral replication and assist in immune evasion. Whereas the pathogenic role of rearrangements in JC polyomavirus has been well established, little is known about BKPyV rearrangements in PyVAN. Objectives: To assess viral microRNA expression and transcriptional control region (TCR) sequence variation in PyVAN patients. Study design: bkv-miR-B1-3p and bkv-miR-B1-5p microRNA expression was quantified in 55 plasma samples from 9 PyVAN patients and 2 controls using specific miRNA assays. TCR architectures among the viral populations in each patient were characterized by massive parallel sequencing. Results: bkv-miR-B1-3p and bkv-miR-B1-5p miRNA expression was established in 85.5% and 98.2% of samples, respectively. On average, an 8.9-fold (bkv-miR-B1-3p) and 8.7-fold (bkv-miR-B1-5p) higher expression levels were detected in PyVAN patients as compared to controls. Rearranged BKPyV strains with duplications and deletions were detected in 7/9 PyVAN patients, but 77.6-99.9% of all sequence reads in all samples represented archetype strains. Conclusions: The frequent detection and increased expression of miRNAs suggest involvement in PyVAN pathogenesis. Despite the predominance of archetype BKPyV strains, the frequent detection of minor rearranged viral populations urges further study on their role in severe kidney disease. Our results suggest that miRNA expression is increased in PyVAN patients, as well as in the presence of rearranged viral strains.
  • Bacos, Karl; Gillberg, Linn; Volkov, Petr; Olsson, Anders H.; Hansen, Torben; Pedersen, Oluf; Gjesing, Anette Prior; Eiberg, Hans; Tuomi, Tiinamaija; Almgren, Peter; Groop, Leif; Eliasson, Lena; Vaag, Allan; Dayeh, Tasnim; Ling, Charlotte (2016)
    Aging associates with impaired pancreatic islet function and increased type 2 diabetes (T2D) risk. Here we examine whether age-related epigenetic changes affect human islet function and if blood-based epigenetic biomarkers reflect these changes and associate with future T2D. We analyse DNA methylation genome-wide in islets from 87 non-diabetic donors, aged 26-74 years. Aging associates with increased DNA methylation of 241 sites. These sites cover loci previously associated with T2D, for example, KLF14. Blood-based epigenetic biomarkers reflect age-related methylation changes in 83 genes identified in human islets (for example, KLF14, FHL2, ZNF518B and FAM123C) and some associate with insulin secretion and T2D. DNA methylation correlates with islet expression of multiple genes, including FHL2, ZNF518B, GNPNAT1 and HLTF. Silencing these genes in beta-cells alter insulin secretion. Together, we demonstrate that blood-based epigenetic biomarkers reflect age-related DNA methylation changes in human islets, and associate with insulin secretion in vivo and T2D.
  • Najumudeen, A. K.; Jaiswal, A.; Lectez, B.; Oetken-Lindholm, C.; Guzman, C.; Siljamaki, E.; Posada, I. M. D.; Lacey, E.; Aittokallio, T.; Abankwa, D. (2016)
    Cancer stem cells (CSCs) are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. Salinomycin is the most established CSC inhibitor. However, its primary mechanistic target is still unclear, impeding the discovery of compounds with similar anti-CSC activity. Here, we show that salinomycin very specifically interferes with the activity of K-ras4B, but not H-ras, by disrupting its nanoscale membrane organization. We found that caveolae negatively regulate the sensitivity to this drug. On the basis of this novel mechanistic insight, we defined a K-ras-associated and stem cell-derived gene expression signature that predicts the drug response of cancer cells to salinomycin. Consistent with therapy resistance of CSC, 8% of tumor samples in the TCGA-database displayed our signature and were associated with a significantly higher mortality. Using our K-ras-specific screening platform, we identified several new candidate CSC drugs. Two of these, ophiobolin A and conglobatin A, possessed a similar or higher potency than salinomycin. Finally, we established that the most potent compound, ophiobolin A, exerts its K-ras4B-specific activity through inactivation of calmodulin. Our data suggest that specific interference with the K-ras4B/calmodulin interaction selectively inhibits CSC.
  • Duy Nguyen, Su; Maaninka, Katariina; Lappalainen, Jani; Nurmi, Katariina; Metso, Jari; Oorni, Katariina; Navab, Mohamad; Fogelman, Alan M.; Jauhiainen, Matti; Lee-Rueckert, Miriam; Kovanen, Petri T. (2016)
    Objective Apolipoprotein A-I (apoA-I) has been shown to possess several atheroprotective functions, including inhibition of inflammation. Protease-secreting activated mast cells reside in human atherosclerotic lesions. Here we investigated the effects of the neutral proteases released by activated mast cells on the anti-inflammatory properties of apoA-I. Approach and Results Activation of human mast cells triggered the release of granule-associated proteases chymase, tryptase, cathepsin G, carboxypeptidase A, and granzyme B. Among them, chymase cleaved apoA-I with the greatest efficiency and generated C-terminally truncated apoA-I, which failed to bind with high affinity to human coronary artery endothelial cells. In tumor necrosis factor--activated human coronary artery endothelial cells, the chymase-cleaved apoA-I was unable to suppress nuclear factor-B-dependent upregulation of vascular cell adhesion molecule-1 (VCAM-1) and to block THP-1 cells from adhering to and transmigrating across the human coronary artery endothelial cells. Chymase-cleaved apoA-I also had an impaired ability to downregulate the expression of tumor necrosis factor-, interleukin-1, interleukin-6, and interleukin-8 in lipopolysaccharide-activated GM-CSF (granulocyte-macrophage colony-stimulating factor)- and M-CSF (macrophage colony-stimulating factor)-differentiated human macrophage foam cells and to inhibit reactive oxygen species formation in PMA (phorbol 12-myristate 13-acetate)-activated human neutrophils. Importantly, chymase-cleaved apoA-I showed reduced ability to inhibit lipopolysaccharide-induced inflammation in vivo in mice. Treatment with chymase blocked the ability of the apoA-I mimetic peptide L-4F, but not of the protease-resistant D-4F, to inhibit proinflammatory gene expression in activated human coronary artery endothelial cells and macrophage foam cells and to prevent reactive oxygen species formation in activated neutrophils. Conclusions The findings identify C-terminal cleavage of apoA-I by human mast cell chymase as a novel mechanism leading to loss of its anti-inflammatory functions. When targeting inflamed protease-rich atherosclerotic lesions with apoA-I, infusions of protease-resistant apoA-I might be the appropriate approach.