Differential deactivation of human dendritic cells by endotoxin desensitization: role of tumor necrosis factor-alpha and prostaglandin E2.
The endotoxin (lipopolysaccharide)-induced cytokine response is followed by a state of unresponsiveness to lipopolysaccharide (LPS) referred to as LPS tolerance or endotoxin desensitization. LPS tolerance, which can be experimentally induced in vitro and in vivo, is also known to occur in septic disease. Here, we evaluated whether dendritic cells (DC), the most potent antigen-presenting cells, are also subject to this phenomenon. Single doses of LPS added at the initiation of DC culture inhibited in a dose-dependent fashion the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), and IL-12, but not the production of IL-8, in response to a second LPS challenge in day-5 DC. In addition, the LPS-induced expression of the CD83 maturation antigen was inhibited in these cells. Moreover, the endocytic activity of DC generated in the presence of LPS was dramatically reduced. DC desensitized with LPS were potent stimulators of T-cell proliferation but poor inducers of interferon-gamma (IFN-gamma) production in the allogeneic mixed leukocyte reaction. TNF-alpha and prostaglandin E2, two major products of LPS stimulation, could replace LPS for the induction of tolerance to LPS. Moreover, treatment of desensitized DC with TNF-alpha plus prostaglandin E2 fully restored CD83 expression and partially restored IL-12 production as well as the IFN-gamma-inducing activity of DC in the mixed leukocyte reaction. Our data show that human DC are highly susceptible to the induction of LPS tolerance, which seems to be a state of differential deactivation in which some functions are impaired whereas others are retained. Tolerization at the level of the professional antigen-presenting cell by inflammatory mediators may play an important role in septic disease and in the origin of cancers associated with chronic inflammation.
Rieser
C
C
Departments of Urology and Internal Medicine, University of Innsbruck, A-6020 Innsbruck, Austria.
Papesh
C
C
Herold
M
M
Böck
G
G
Ramoner
R
R
Klocker
H
H
Bartsch
G
G
Thurnher
M
M
D015703:Antigens, CD; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D015232:Dinoprostone / Q000494:pharmacology*; D004361:Drug Tolerance; D004705:Endocytosis; D006801:Humans; D007108:Immune Tolerance; D007111:Immunity, Cellular; D007136:Immunoglobulins / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D000097802:CD83 Antigen
D015703:Antigens, CD; D015232:Dinoprostone; D007136:Immunoglobulins; D007371:Interferon-gamma; D016753:Interleukin-10; D018664:Interleukin-12; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D000097802:CD83 Antigen