Effect of trichostatin A on human T cells resembles signaling abnormalities in T cells of patients with systemic lupus erythematosus: a new mechanism for TCR zeta chain deficiency and abnormal signaling.
Trichostatin A (TSA) is a potent reversible inhibitor of histone deacetylase, and it has been reported to have variable effects on the expression of a number of genes. In this report, we show that TSA suppresses the expression of the T cell receptor zeta chain gene, whereas, it upregulates the expression if its homologous gene Fc(epsilon) receptor I gamma chain. These effects are associated with decreased intracytoplasmic-free calcium responses and altered tyrosine phosphorylation pattern of cytosolic proteins. Along with these effects, we report that TSA suppresses the expression of the interleukin-2 gene. The effects of TSA on human T cells are predominantly immunosuppressive and reminiscent of the signaling aberrations that have been described in patients with systemic lupus erythematosus.
Nambiar
Madhusoodana P
MP
Department of Cellular Injury, Walter Reed Army Institute of Research, Building 503, Robert Grant Road, Silver Spring, Maryland 20910-7500, USA.
Warke
Vishal G
VG
Fisher
Carolyn U
CU
Tsokos
George C
GC
D000293:Adolescent; D000328:Adult; D017252:CD3 Complex / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D036383:Ephrin-A2 / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency* / Q000187:drug effects / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency* / Q000187:drug effects / Q000378:metabolism; D017455:Receptors, IgE / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D017252:CD3 Complex; D004791:Enzyme Inhibitors; D036383:Ephrin-A2; D006877:Hydroxamic Acids; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D017455:Receptors, IgE; C054979:antigen T cell receptor, zeta chain; C012589:trichostatin A; D014443:Tyrosine