NF-κB Regulates Expression of the MHC Class I-Related Chain A Gene in Activated T Lymphocytes

Abstract

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.

Molecular Regulation of MHC Class I Chain-Related Protein A Expression after HDAC-Inhibitor Treatment of Jurkat T Cells

“…We conclude that NF-B p65 activity is not essential for HDAC-i-mediated MICA/B expression in Jurkat T cells. It has been shown that NF-B activity is important for MICA expression of activated peripheral blood T lymphocytes (44) and our data does not argue against the ability of NF-B activity to further regulate MICA expression.…”

Nasopharyngeal Cancer – An Expanding Puzzle – Claiming for Answers

“…Furthermore, a recent study demonstrated the existence of a binding site in the long intron 1 of the MICA gene for NF-kappaB (Molinero, Fuertes et al 2004). It has been shown that physiologic concentrations of male hormones (androgens) cause prolonged NF-kappaB DNA binding activities, which are diminished by vitamins C and E (Ripple, Henry et al 1999)and estrogen inhibits NF-kappa B activity (Ghisletti, Meda et al 2005;Kalaitzidis and Gilmore 2005).…”

Pas de deux: Natural Killer Receptors and MHC Class I Ligands in Primates

“…Interestingly, expression of MIC genes can be upregulated upon certain stimuli ('cell stress') such as viral infections [33], oxidative stress [34], or heat shock [35]. Furthermore, expression is activated by the NF-kappa B pathway [36] and by DNA damage [37]. MICA and MICB molecules could be shown to be ligands for the strong activating receptor NKG2D (KLRK1) [38,39], which is expressed on NK cells, and T lymphocytes, and macrophages.…”