In:
The Journal of Immunology, The American Association of Immunologists, Vol. 173, No. 9 ( 2004-11-01), p. 5583-5590
Kurzfassung:
MHC class I-related chain A gene (MICA) is a stress-regulated, HLA-related molecule which exhibits a restricted pattern of expression. MICA protein is up-regulated on different tumor cells, and is recognized by the lectin-like NKG2D molecule expressed by cytotoxic γδ T lymphocytes, CD8+ αβ T lymphocytes, and NK cells. Although MICA is not expressed on resting lymphocytes, we demonstrated that it is induced on activated T cells. Because NF-κB is actively involved in T cell activation, and is constitutively activated in many tumors, here we investigated whether NF-κB may modulate MICA expression. Treatment with the NF-κB inhibitor sulfasalazine (Sz) resulted in a dose-dependent inhibition of MICA expression in anti-CD3- and anti-CD28/PMA-activated T lymphocytes, as assessed by Western blot and RT-PCR analysis. Moreover, Sz also down-regulated MICA expression on epithelial tumor HeLa cells. MICA expression was accompanied by a Sz-sensitive IκBα degradation. EMSA with nuclear extracts from anti-CD3- and anti-CD28/PMA-stimulated T lymphocytes demonstrated the binding of a potential NF-κB family transcription factor to a MICA gene intron 1-derived oligonucleotide that contains a putative κB binding site. Supershift assays demonstrated the presence of p65(RelA)/p50 heterodimers and p50/p50 homodimers in the NF-κB complexes bound to the κB-MICA oligonucleotide. Transient transfection of HeLa cells with p65(RelA) up-regulated MICA expression, as assessed by Western blot and flow cytometry analysis. Hence, we conclude that NF-κB regulates MICA expression on activated T lymphocytes and HeLa tumor cells, by binding to a specific sequence in the long intron 1 of the MICA gene. This constitutes the first description of a transcription factor that regulates MICA gene expression.
Materialart:
Online-Ressource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.173.9.5583
Sprache:
Englisch
Verlag:
The American Association of Immunologists
Publikationsdatum:
2004
ZDB Id:
1475085-5
