Ribotoxic stress activates p38 and JNK kinases and modulates the antigen-presenting activity of dendritic cells.
Initiation of adaptive immunity requires activation of dendritic cells (DC) by "danger" signals. This study examines the functional consequences of activating a cellular stress response in human DC. Anisomycin, a potent inducer of this "stress" response, selectively activates p38 kinase in DC at low concentrations, and both p38 kinases and JNKs at higher concentrations. Activation of p38, was accompanied by an increase in the potency of dendritic cells to activate T cells. In contrast to LPS, anisomycin had no effect on the expression of several DC activation markers. Anisomycin synergised with LPS in driving release of IL-12 and TNF-alpha. Anisomycin also enhanced the formation of clusters between DC and T cells. Enhanced cytokine release and clustering were both inhibited by the selective p38 alpha and p38 beta inhibitor SB203580. This study demonstrates that the cellular stress response, mediated via p38 kinases, plays an important role in the regulation of several aspects of DC function.
Bunyard
Peter
P
Department of Immunology and Molecular Biology, Windeyer Institute for Medical Sciences, University College London, 46 Cleveland Street, London W1T 4JF, UK.
Handley
Matthew
M
Pollara
Gabriel
G
Rutault
Karine
K
Wood
Isabelle
I
Chaudry
Manika
M
Alderman
Charles
C
Foreman
John
J
Katz
David R
DR
Chain
Benjamin M
BM
D000841:Anisomycin / Q000633:toxicity; D017951:Antigen Presentation; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000633:toxicity; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018448:Models, Immunological; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D000841:Anisomycin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases