Histone deacetylase inhibitors: a new class of immunosuppressors targeting a novel signal pathway essential for CD154 expression.
Here we report that histone deacetylase inhibitors (HDAC-i) comprise a new class of immunosuppressive agents. HDAC-i inhibited CD4 T-cell proliferation in a dose-dependent manner, which was not caused by apoptosis or decreased viability. Although early intracellular signals such as tyrosine kinase activity and elevation of intracellular calcium concentration were not affected, the characteristic aggregation of T cells following activation was completely abrogated. This correlated with diminished activation-induced expression of the adhesion molecules. HDAC-i furthermore inhibited activation-induced CD25 and CD154 expression on CD4 cells, without affecting induction of CD69. HDAC-i inhibited CD154 expression by a mechanism distinctly different from cyclosporine-mediated inhibition. HDAC-i thus inhibited interleukin 2 (IL-2)-induced CD154 expression on effector T cells and constitutively expressed CD154 on various tumor cells, events that were not affected by cyclosporine. Additional studies showed that HDAC-i treatment inhibited c-Myc expression, which was further shown to be important for CD154 gene activation. These results demonstrate pronounced T-cell inhibitory activity of HDAC-i, which may form the basis of novel therapeutic interventions against autoimmune diseases and allograft rejection.
Skov
Søren
S
Cell Cybernetics Laboratory, Department of Medical Microbiology and Immunology, The Panum Institute, University of Copenhagen, Denmark. s.skov@immi.ku.dk
Rieneck
Klaus
K
Bovin
Lone Frier
LF
Skak
Kresten
K
Tomra
Søren
S
Michelsen
Birgitte K
BK
Ødum
Niels
N
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001327:Autoimmune Diseases / Q000517:prevention & control; D023201:CD40 Ligand / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D016259:Genes, myc / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D015375:Receptors, Interleukin-2 / Q000235:genetics; D016196:S Phase; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000276:immunology
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D023201:CD40 Ligand