title: HSP110 induces "danger signals" upon interaction with antigen presenting cells and mouse mammary carcinoma.
abstract: HSP110 is a large molecular weight heat shock protein highly capable of chaperoning large proteins. When chaperoning tumour antigens, HSP110 is capable of eliciting effective anti-tumour immune responses. In the present study, we have determined whether such immunoadjuvant properties of HSP110 stem from its ability to induce "danger signals" through interaction with antigen presenting cells (APCs) and with tumour cells. In the previous studies, endotoxin contamination of HSP preparations was always a matter of concern and controversy. Therefore, we prepared recombinant HSP110 with low endotoxin concentration at which LPS did not have any effect on dendritic cells (DCs). We then evaluated the ability of the HSP110 to induce "danger signals" while interacting with APCs or mouse mammary carcinoma cell line (MMC), as evaluated by modulation of cell surface receptors and cytokines involved in innate and adaptive immune responses. We also performed competition studies in order to rule out contribution of endotoxin in HSP110 preparations while interacting with DCs and MMC. We showed that low endotoxin HSP110 induced DCs to up-regulate the expression of MHC class II, CD40 and CD86 molecules, and to secrete pro-inflammatory cytokines IL-6, IL-12 and TNF-alpha. Importantly, HSP110 induced MMC to secrete IL-12 and elevate secretion of IL-6 and expression of CD40 molecule. These findings demonstrate that HSP110 acts as a "danger signal" through its interaction with DCs and tumour cells, regardless of its endotoxin component. These immunoadjuvant properties of HSP110 suggest that pre-existing immunity in tumour-bearing individuals,may be due to the release of HSPs from tumours upon necrosis alerting the immune system against the tumours.
authors.affiliation: Department of Microbiology & Immunology, Virginia Commonwealth University, Massey Cancer Center, Box 980037, Richmond, VA 23298, USA. mmanjili@vcu.edu
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
authors.forename: Juneui
authors.initials: J
authors.lastname: Park
authors.forename: John G
authors.initials: JG
authors.lastname: Facciponte
authors.forename: John R
authors.initials: JR
authors.lastname: Subjeck
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology; D051940:B7-2 Antigen; D001853:Bone Marrow; D001943:Breast Neoplasms; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology; D002277:Carcinoma; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005802:Genes, MHC Class II; D050957:HSP110 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000008:administration & dosage / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D050957:HSP110 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D000949:Histocompatibility Antigens Class II; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12