Proteomic Analyses of the Effects of Drugs of Abuse on Monocyte-Derived Mature Dendritic Cells

Reynolds, Jessica L.; Mahajan, Supriya D.; Aalinkeel, Ravikunar; Nair, Bindukumar; Sykes, Donald E.; Schwartz, Stanley A.

doi:10.1080/08820130902874110

Cited by 15 publications

(11 citation statements)

References 90 publications

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“…Moreover, recent studies have determined that cocaine enhances HIV-1 induced CD4+ T cell apoptosis and contributes to disease progression among drug users (Pandhare et al 2014). Proteomics analyses of monocyte-derived mature dendritic cells demonstrated the effects of cocaine in enhancing HIV-replication with over-expression of important proteins such as aldolase, enolase, cathepsin S, HSP90, MEK1, MEK2 among others (Reynolds et al 2009). Studies in human astrocytes exposed to cocaine also demonstrated that increased enolase, aldolase, HSP60, Anexin I among others (Reynolds et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Cocaine Potentiates Cathepsin B Secretion and Neuronal Apoptosis from HIV-Infected Macrophages

Zenón

Segarra

Gonzalez

et al. 2014

J Neuroimmune Pharmacol

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Substance abuse is a risk factor for HIV infection and progression to AIDS. Recent evidence establishes that cocaine use promotes brain perivascular macrophage infiltration and microglia activation. The lysosomal protease cathepsin B is increased in monocytes from patients with HIV dementia and its secretion induces 10-15% of neurotoxicity. Here we asked if cocaine potentiates cathepsin B secretion from HIV-infected monocyte-derived macrophages (MDM) and its effect in neuronal apoptosis. Samples of plasma, CSF, and post-mortem brain tissue from HIV positive patients that used cocaine were tested for cathepsin B and its inhibitors to determine the in vivo relevance of these findings. MDM were inoculated with HIV-1ADA, exposed to cocaine, and the levels of secreted and bioactive cathepsin B and its inhibitors were measured at different time-points. Cathepsin B expression (p<0.001) and activity (p<0.05) increased in supernatants from HIV-infected cocaine treated MDM compared with HIV-infected cocaine negative controls. Increased levels of cystatin B expression was also found in supernatants from HIV-cocaine treated MDM (p<0.05). A significant increase in 30% of apoptotic neurons was obtained that decreased to 5% with the specific cathepsin B inhibitor (CA-074) or with cathepsin B antibody. Cathepsin B was significantly increased in the plasma and post-mortem brain tissue of HIV/cocaine users over non-drug users. Our results demonstrated that cocaine potentiates cathepsin B secretion in HIV-infected MDM and increase neuronal apoptosis. These findings provide new evidence that cocaine synergize with HIV-1 infection in increasing cathepsin B secretion and neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Cocaine Potentiates Cathepsin B Secretion and Neuronal Apoptosis from HIV-Infected Macrophages

Zenón

Segarra

Gonzalez

et al. 2014

J Neuroimmune Pharmacol

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“…HIV-1 directly affects dendritic cells (DC) and leads to dysfunction of immune system manifested by increased levels of inflammatory cytokines, chemokines and neurotoxin such as quinolinic acid and arachidonic acid (AA) [9], [10]. Increasing evidence suggests that DCs play a major role in the defense against HIV infection and illicit drug such as cocaine [11]–[13]. Immature dendritic cells (IDC) specialize in capturing and processing antigens and plays wide role in cell maturation, migration to CD4+ T cells, and T cell activation [14].…”

Section: Introductionmentioning

confidence: 99%

Immunopathogenesis of HIV Infection in Cocaine Users: Role of Arachidonic Acid

et al. 2014

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Arachidonic acid (AA) is known to be increased in HIV infected patients and illicit drug users are linked with severity of viral replication, disease progression, and impaired immune functions. Studies have shown that cocaine accelerates HIV infection and disease progression mediated by immune cells. Dendritic cells (DC) are the first line of antigen presentation and defense against immune dysfunction. However, the role of cocaine use in HIV associated acceleration of AA secretion and its metabolites on immature dendritic cells (IDC) has not been elucidated yet. The aim of this study is to elucidate the mechanism of AA metabolites cyclooxygenase-2 (COX-2), prostaglandin E2 synthetase (PGE2), thromboxane A2 receptor (TBXA2R), cyclopentenone prostaglandins (CyPG), such as 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), 14-3-3 ζ/δ and 5-lipoxygenase (5-LOX) mediated induction of IDC immune dysfunctions in cocaine using HIV positive patients. The plasma levels of AA, PGE2, 15d-PGJ2, 14-3-3 ζ/δ and IDC intracellular COX-2 and 5-LOX expression were assessed in cocaine users, HIV positive patients, HIV positive cocaine users and normal subjects. Results showed that plasma concentration levels of AA, PGE2 and COX-2, TBXA2R and 5-LOX in IDCs of HIV positive cocaine users were significantly higher whereas 15d-PGJ2 and 14-3-3 ζ/δ were significantly reduced compared to either HIV positive subjects or cocaine users alone. This report demonstrates that AA metabolites are capable of mediating the accelerative effects of cocaine on HIV infection and disease progression.

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“…Subsequent evaluation and selection by several quality criteria (see Materials and Methods) led to identification of 194 peptides derived from 64 different proteins (Supplementary Table 1, only online). Proteomic profiling of human monocyte-derived dendritic cells revealed that a number of these peptides are derived from ubiquitously expressed proteins (e.g., from house-keeping, cytoskeletal, or matrix proteins) 34,35,36,37,38,39,40,41,42,43. These include ribosomal proteins, actin and actin-related proteins, aldolase A, annexin A2, β2-micoglobulin, calmodulin, cathepsin proteins, superoxide dismutase, systatins, elonase 1, galectin 1, glycolysis-related enzymes, histones, HSP70, IL-1RA, kynureninase, macrophage migrating inhibitory factor, peroxiredoxin 6, phosphoglycerated kinase 1, S100 calcium binding proteins and vimentin.…”

Section: Resultsmentioning

confidence: 99%

Identification of Pancreatic Cancer-Associated Tumor Antigen from HSP-Enriched Tumor Lysate-Pulsed Human Dendritic Cells

et al. 2014

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PurposeVaccine strategies utilizing dendritic cells (DCs) to elicit anti-tumor immunity are the subject of intense research. Although we have shown that DCs pulsed with heat-treated tumor lysate (HTL) induced more potent anti-tumor immunity than DCs pulsed with conventional tumor lysate (TL), the underlying molecular mechanism is unclear. In order to explore the molecular basis of this approach and to identify potential antigenic peptides from pancreatic cancer, we analyzed and compared the major histocompatibility complex (MHC) ligands derived from TL- and HTL-pulsed dendritic cells by mass spectrophotometry.Materials and MethodsHuman monocyte-derived dendritic cells were pulsed with TL or HTL prior to maturation induction. To delineate differences of MHC-bound peptide repertoire eluted from DCs pulsed with TL or HTL, nanoflow liquid chromatography-electrospray ionization-tandem mass spectrometry (nLC-ESI-MS-MS) was employed.ResultsHTL, but not TL, significantly induced DC function, assessed by phenotypic maturation, allostimulation capacity and IFN-γ secretion by stimulated allogeneic T cells. DCs pulsed with TL or HTL displayed pancreas or pancreatic cancer-related peptides in context of MHC class I and II molecules. Some of the identified peptides had not been previously reported as expressed in pancreatic cancer or cancer of other tissue types.ConclusionOur partial lists of MHC-associated peptides revealed the differences between peptide profiles eluted from HTL-and TL-loaded DCs, implying that induced heat shock proteins in HTL chaperone tumor-derived peptides enhanced their delivery to DCs and promoted cross-presentation by DC. These findings may aid in identifying novel tumor antigens or biomarkers and in designing future vaccination strategies.

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Proteomic Analyses of the Effects of Drugs of Abuse on Monocyte-Derived Mature Dendritic Cells

Cited by 15 publications

References 90 publications

Cocaine Potentiates Cathepsin B Secretion and Neuronal Apoptosis from HIV-Infected Macrophages

Cocaine Potentiates Cathepsin B Secretion and Neuronal Apoptosis from HIV-Infected Macrophages

Immunopathogenesis of HIV Infection in Cocaine Users: Role of Arachidonic Acid

Identification of Pancreatic Cancer-Associated Tumor Antigen from HSP-Enriched Tumor Lysate-Pulsed Human Dendritic Cells

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