[Impact of cyclosporine A on the expression of T-bet, GATA-3, relevant signal transduction molecules, cytokine and Th1/Th2 balance in patients with chronic aplastic anemia].
The study was aimed to explore the effects of T-bet (T-box expressed in T cell), GATA-3(GATA binding protein 3) and relevant signal transduction pathways on the immune-related pathogenesis of chronic aplastic anemia (CAA), and to investigate the immunological regulation mechanism in the treatment of CAA by using cyclosporine A (CsA) at the level of Th cell imbalance, transcriptional factors, and relevant signal pathways. The real-time fluorescent quantitative polymerase chain reaction (real-time FQ-PCR) was used to determine the mRNA expression of T-bet, GATA-3, signal transducers and activators of transcription 4 (STAT4) and signal transducers and activators of transcription 6 (STAT6) in peripheral blood mononuclear cell (PBMNC) of CAA patients before and after treatment with CsA; the flow cytometry (FCM) and enzyme linked immunosorbent assay (ELISA) were used to determine the Th1/Th2 proportion in peripheral blood, and levels of IFN-γ, IL-12 and IL-4 in PBMNC-cultured supernatant. Healthy people were included to test the above indexes. The results showed that the mRNA expression of PBMNC T-bet, STAT4, T-bet/GATA-3 ratio, Th1 proportion, Th1/Th2 ratio and levels of IFN-γ and IL-12 in PBMNC-cultured supernatant of CAA patients were significantly higher than those of healthy people (p < 0.01). After treating with CsA for 6 months of CsA treatment, expression of T-bet, STAT4, T-bet/GATA-3 ratio, Th1 proportion, IFN-γ and IL-12 levels were lower than before, however, the expression of T-bet, STAT4, T-bet/GATA-3 ratio, Th1 proportion and IFN-γ had not been reduced to normal state. Compared to healthy people, no significant difference existed in the mRNA expression of GATA-3, STAT6, Th2 proportion, as well as level of IL-4 before and after treatment (p>0.05). It is concluded that the abnormal activation of IFN-γ/T-bet and IL-12/STAT4 pathways, as well as Th balance deviating to Th1 excursion play vital roles in the immunological pathogenesis of AA. CsA lowers the abnormal activation of IFN-γ/T-bet and IL-12/STAT4 pathways to correct Th1 hyperpolarization, which may reduce the abnormally activated cell-mediated immunity and relax hematopoietic depression of AA patients.
Department of Hematology, Jiangsu Provincial Hospital of Chinese Traditional Medicine, Nanjing University of Chinese Traditional Medicine, Nanjing 210029, Jiangsu Province, China.
Jun
J
Li
Yong-Ming
YM
Zhou
Ming-Hui
MH
Hu
Wei-Ling
WL
Sun
Zhi-Zhong
ZZ
Xue
D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D050990:GATA3 Transcription Factor / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050797:STAT4 Transcription Factor / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism*; D018417:Th1 Cells / Q000187:drug effects*; D018418:Th2 Cells / Q000187:drug effects*; D055815:Young Adult; D000098815:T-bet Transcription Factor
D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C508598:IL4 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D016572:Cyclosporine