T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia.
In aplastic anemia, immune destruction of hematopoietic cells results in bone marrow failure. Type 1 cytokines, especially IFN-gamma, have been implicated in the pathophysiology of T-cell-mediated, Fas-mediated stem cell apoptosis of hematopoietic cells. Here, we show that the transcription factor T-bet (T-box expressed in T cells) is increased in T cells from patients with aplastic anemia. Patients' T-bet bound directly to the proximal site of the IFN-gamma promoter without any prior stimulation, in contrast to healthy controls. Increased levels of Itk kinase participated in T-bet up-regulation and active transcription of the IFN-gamma gene observed in these patients. Blocking PKC-, a kinase that lies downstream of Itk kinase, decreased T-bet protein and IFN-gamma intracellular levels. These data suggest that the increased IFN-gamma levels observed in aplastic anemia patients are the result of active transcription of the IFN-gamma gene by T-bet. Blocking the transcription of the IFN-gamma gene with kinase inhibitors might lead to the development of novel therapeutic agents for patients with aplastic anemia and other autoimmune diseases.
Solomou
Elena E
EE
Hematology Branch, National Heart, Lung, and Blood Institute/NIH, Bldg 10, CRC, Rm 3E5216, 10 Center Drive, Bethesda, MD 20892, USA. solomoue@nhlbi.nih.gov
Keyvanfar
Keyvan
K
Young
Neal S
NS
D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000097:blood* / Q000235:genetics / Q000276:immunology; D002467:Cell Nucleus / Q000502:physiology; D002648:Child; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D008297:Male; D008875:Middle Aged; D018123:Receptors, Interleukin / Q000097:blood; D053707:Receptors, Interleukin-12; D020825:T-Box Domain Proteins; D013601:T-Lymphocytes / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation; D000098815:T-bet Transcription Factor
D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D007371:Interferon-gamma