Monocyte-derived DC primed with TLR agonists secrete IL-12p70 in a CD40-dependent manner under hyperthermic conditions.
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.
Peng
Judy C
JC
Centre for Immunology and Cancer Research, Princess Alexandra Hospital, Division of Chemical Engineering, University of Queensland, Australia.
Hyde
Claire
C
Pai
Saparna
S
O'Sullivan
Brendan J
BJ
Nielsen
Lars K
LK
Thomas
Ranjeny
R
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
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