Dataset Information

Human resistin, a proinflammatory cytokine, shows chaperone-like activity.

ABSTRACT: Resistin, a cysteine-rich adipocytokine, proposed as a link between obesity and diabetes in mice, was shown as a proinflammatory molecule in humans. We earlier reported that human resistin (hRes), a trimer, was resistant to heat and urea denaturation, existed in an oligomeric polydispersed state, and showed a concentration-dependent conformational change. These properties and an intimate correlation of hRes expression with cellular stress prompted us to investigate hRes as a possible chaperone. Here, we show that recombinant human resistin was able to protect the heat-labile enzymes citrate synthase and Nde1 from thermal aggregation and inactivation and was able to refold and restore their enzymatic activities after heat/guanidinium chloride denaturation. Furthermore, recombinant human resistin could bind misfolded proteins only. Molecular dynamics-based association-dissociation kinetics of hRes subunits pointed to resistin being a molecular chaperone. Bis-ANS, which blocks surface hydrophobicity, abrogated the chaperone activity of hRes, establishing the importance of surface hydrophobicity for chaperone activity. Replacement of Phe49 with Tyr (F49YhRes), a critical residue within the hydrophobic patch of hRes, although it could prevent thermal aggregation of citrate synthase and Nde1, was unable to refold and restore their activities. Treatment of U937 cells with tunicamycin/thapsigargin resulted in reduced hRes secretion and concomitant localization in the endoplasmic reticulum. Escherichia coli transformants expressing hRes could be rescued from thermal stress, pointing to hRes's chaperone-like function in vivo. HeLa cells transfected with hRes showed protection from thapsigargin-induced apoptosis. In conclusion, hRes, an inflammatory protein, additionally exhibited chaperone-like properties, suggesting a possible link between inflammation and cellular stress.

SUBMITTER: Suragani M

PROVIDER: S-EPMC3870731 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Human resistin, a proinflammatory cytokine, shows chaperone-like activity.

Suragani Madhuri M Aadinarayana Varma D VD Pinjari Aleem Basha AB Tanneeru Karunakar K Guruprasad Lalitha L Banerjee Sharmistha S Pandey Saurabh S Chaudhuri Tapan K TK Ehtesham Nasreen Zafar NZ

Proceedings of the National Academy of Sciences of the United States of America 20131126 51

Resistin, a cysteine-rich adipocytokine, proposed as a link between obesity and diabetes in mice, was shown as a proinflammatory molecule in humans. We earlier reported that human resistin (hRes), a trimer, was resistant to heat and urea denaturation, existed in an oligomeric polydispersed state, and showed a concentration-dependent conformational change. These properties and an intimate correlation of hRes expression with cellular stress prompted us to investigate hRes as a possible chaperone. ...[more]

PMID: 24282299

Similar Datasets

Project description:UnlabelledSimilar to H5N1 viruses, A(H7N9) influenza viruses have been associated with severe respiratory disease and fatal outcomes in humans. While high viral load, hypercytokinemia, and pulmonary endothelial cell involvement are known to be hallmarks of H5N1 virus infection, the pathogenic mechanism of the A(H7N9) virus in humans is largely unknown. In this study, we assessed the ability of A(H7N9) virus to infect, replicate, and elicit innate immune responses in both human bronchial epithelial cells and pulmonary microvascular endothelial cells, compared with the abilities of seasonal H3N2, avian H7N9, and H5N1 viruses. In epithelial cells, A(H7N9) virus replicated efficiently but did not elicit robust induction of cytokines like that observed for H5N1 virus. In pulmonary endothelial cells, A(H7N9) virus efficiently initiated infection; however, no released infectious virus was detected. The magnitudes of induction of host cytokine responses were comparable between A(H7N9) and H5N1 virus infection. Additionally, we utilized differentiated human primary bronchial and tracheal epithelial cells to investigate cellular tropism using transmission electron microscopy and the impact of temperature on virus replication. Interestingly, A(H7N9) virus budded from the surfaces of both ciliated and mucin-secretory cells. Furthermore, A(H7N9) virus replicated to a significantly higher titer at 37 °C than at 33 °C, with improved replication capacity at 33 °C compared to that of H5N1 virus. These findings suggest that a high viral load from lung epithelial cells coupled with induction of host responses in endothelial cells may contribute to the severe pulmonary disease observed following H7N9 virus infection. Improved adaptation of A(H7N9) virus to human upper airway poses an important threat to public health.ImportanceA(H7N9) influenza viruses have caused over 450 documented human infections with a 30% fatality rate since early 2013. However, these novel viruses lack many molecular determinants previously identified with mammalian pathogenicity, necessitating a closer examination of how these viruses elicit host responses which could be detrimental. This study provides greater insight into the interaction of this virus with host lung epithelial cells and endothelial cells, which results in high viral load, epithelial cell death, and elevated immune response in the lungs, revealing the mechanism of pathogenesis and disease development among A(H7N9)-infected patients. In particular, we characterized the involvement of pulmonary endothelial cells, a cell type in the human lung accessible to influenza virus following damage of the epithelial monolayer, and its potential role in the development of severe pneumonia caused by A(H7N9) infection in humans.

Project description:Bullous pemphigoid (BP) is a rare autoimmune skin blistering disease, characterized by the presence of autoantibodies against hemidesmosomal autoantigens. Cytokine expression is altered in BP patients, and several of these differently expressed cytokines, including IL-1α, IL-1β, IL-8, and TNF-α, contribute to disease pathogenesis. Since genetic polymorphisms in the genes of these cytokines might be implicated in susceptibility to BP disease, we aimed at testing this implication in susceptibility to BP in an Iranian cohort. Blood samples were collected from the subjects and genomic DNA was extracted. To detect the single nucleotide polymorphisms (SNPs), IL-1α (rs1800587), IL-1β (rs1143627, rs16944, rs1143634), IL-8 (rs4073), and TNF-α (rs1799964, rs1800630, rs1799724, and rs361525) genes were genotyped in BP patients and healthy controls as well as IL-8 (rs4073) in pemphigus vulgaris (PV) patients. Quantitative gene expression was evaluated by RT-PCR analysis. A significant difference was observed in the distribution of genotypes or alleles of IL-8 SNP between the BP patients and controls. The A-allele of IL-8 SNP is significantly more prevalent in the control individuals compared to the BP patient. To further validate this observation, we included PV patients as an additional control. Again, the A-allele of IL-8 SNP is significantly more prevalent in the PV compared to the BP patients. While we observed a trend toward significant differences regarding alleles of TNF-α rs1799724 as well as alleles of TNF-α rs1799964, this difference was, however, not evident after correction for multiple analysis. There was no significant difference in all other studied SNPs. In contrast to IL-1α, IL-1β, and TNF-α, IL-8 gene expression levels were significantly higher in the patients than that of controls. The minor allele in IL-8 SNP might play a protective role in susceptibility to BP in Iranian patients. Although higher expression levels of IL-8 gene was found in the patients compared with healthy controls, these levels, however, suggest no association with the examined polymorphism. Moreover, further investigation revealed an elevation in gene expression between wild and polymorphic genotypes of IL-1α rs1800587 and TNF-α rs361525 in the patient group and these SNPs are therefore associated with altering the levels of gene expression.

Project description:Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with the human malignancy Kaposi's sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman's disease. KSHV establishes lytic infection of monocytes in vivo, which may represent an important cellular reservoir during KS disease progression. KS tumors consist of latently infected endothelial cells; however, lytic phase gene products are important for KS onset. Early KS lesion progression is driven by proinflammatory cytokines supplied by immune cell infiltrates including T cells and monocytes. KSHV-infected monocytes may supply the lytic viral products and the inflammatory milieu conducive to KS tumor progression. To establish successful infection, KSHV extensively modulates the host immune system. KSHV antigens activate both innate and adaptive immune responses including KSHV-specific T cells, but lifelong infection is still established. Programmed death ligand 1 (PD-L1) is a prosurvival cell surface protein that suppresses T-cell-mediated killing. PD-L1 is variably present on various tumor cells and is a targetable marker for cancer treatment. We show that KSHV infection of human monocytes increases PD-L1 expression and transcription in a dose-dependent manner. We also saw evidence of lytic gene expression in the KSHV-infected monocytes. Intact KSHV is needed for full PD-L1 response in human monocytes. KSHV induces a general proinflammatory cytokine milieu including interleukins 1?, 1?, and 6, which have been implicated in early KS lesion progression. KSHV-mediated PD-L1 increase may represent a novel mechanism of KSHV-mediated immune modulation to allow for virus survival and eventually malignant progression.IMPORTANCE KSHV is the etiologic agent of Kaposi's sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman's disease. Programmed death ligand 1 (PD-L1) is an immunosuppressive cell surface marker that inhibits T cell activation. We report that KSHV infection of primary human monocytes upregulates PD-L1 transcription and protein expression. Analysis of the cytokine and chemokine milieu following KSHV infection of monocytes revealed that KSHV induces interleukins 1?, 1?, and 6, all of which have been implicated in KS development. Our work has identified another potential immune evasion strategy for KSHV and a potential target for immunotherapy of KSHV-derived disease.

Dataset Information

Human resistin, a proinflammatory cytokine, shows chaperone-like activity.

Publications

Human resistin, a proinflammatory cytokine, shows chaperone-like activity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure