title: Monocyte-derived DC primed with TLR agonists secrete IL-12p70 in a CD40-dependent manner under hyperthermic conditions.
abstract: Fever is an evolutionarily conserved mechanism to improve survival during infection. Previous studies have shown that feverlike temperatures directly enhance the function of murine bone marrow-derived dendritic cells (DCs). In the present study, we examined the response of human monocyte-derived DC to 39.5 degrees C hyperthermia. When primed with toll-like receptor agonists or bacterial extract but not proinflammatory cytokines, hyperthermia specifically enhanced secretion of interleukin (IL)-12p70 by DC, without altering the secretion of IL-10, tumor necrosis factor alpha or IL-1beta. These DC induced significantly higher levels of T-cell proliferation and interferon gamma production in assays of antigen presentation and MLR. Endogenous heat-sock protein 70 colocalized with CD40 in DC exposed to hyperthermic conditions. Recombinant CD40-Fc fusion protein blocked the increase in IL-12p70 secretion by DC primed with bacterial extract and hyperthermia. Thus, DC primed with toll-like receptor-agonists respond to hyperthermia with increased IL-12p70 secretion, mediated by heat-shock protein binding and activation of CD40. The data have important applications for clinical immunotherapy and the mechanism of fever.
authors.affiliation: Centre for Immunology and Cancer Research, Princess Alexandra Hospital, Division of Chemical Engineering, University of Queensland, Australia.
authors.forename: Judy C
authors.initials: JC
authors.lastname: Peng
authors.forename: Claire
authors.initials: C
authors.lastname: Hyde
authors.forename: Saparna
authors.initials: S
authors.lastname: Pai
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: O'Sullivan
authors.forename: Lars K
authors.initials: LK
authors.lastname: Nielsen
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D000942:Antigens, Bacterial / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006684:HLA-DR Antigens / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism*; D015847:Interleukin-4 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010457:Peptidoglycan / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013745:Tetanus Toxoid / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists*; D000097802:CD83 Antigen
chemical_list: D000942:Antigens, Bacterial; D015703:Antigens, CD; D051940:B7-2 Antigen; D019013:CD40 Antigens; D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006684:HLA-DR Antigens; D018840:HSP70 Heat-Shock Proteins; D007136:Immunoglobulins; D007371:Interferon-gamma; D018664:Interleukin-12; D015847:Interleukin-4; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010457:Peptidoglycan; D011070:Poly I-C; D011993:Recombinant Fusion Proteins; D013745:Tetanus Toxoid; D051193:Toll-Like Receptors; D000097802:CD83 Antigen; C499839:CD40Ig protein, recombinant; C034206:Ribomunyl