Impact of C-rel inhibition of cord blood-derived B-, T-, and NK cells

Abstract

The c-Rel transcription factor is a unique member of the nuclear factor (NF)-jB family that has a role in curtailing the proliferation, differentiation, cytokine production, and overall activity of B-and T-cells. In addition, c-Rel is a key regulator of apoptosis in that it influences the expression of anti-apoptotic genes such as Bcl-2 and Bcl-xL; conversely, inhibition of c-Rel increases cell apoptosis. To better understand the relationship between c-Rel expression and effects on B-and T-cell expansion, the current study evaluated c-Rel expression in cord blood mononuclear cells. This particular source was selected as cord blood is an important source of cells used for transplantation and immunotherapy, primarily in treating leukemias. As stem cell factor (SCF) and FLT3 are important agents for hematopoietic stem cell expansion, and cytokines like interleukin (IL)-2, -7, and -15 are essential for T-and B-(and also NK) cell development and proliferation, the current study evaluated c-Rel expression in cord blood mononuclear cells and CD34 þ cells, as well as effects on B-, T-, and NK cells associated with alterations in c-Rel expression, using flow cytometry and PCR. The results showed c-Rel expression increased among cells cultured in the presence of SCF and FLT3 but was reduced when IL-2, IL-7, and IL-15 were used all together. Further, inhibition of c-Rel expression by siRNA reduced cord blood-derived B-, T-, and NK cell differentiation and expansion. These results indicated that with cells isolated from cord blood, c-Rel has an important role in B-, T-, and NK cell differentiation and, further, that agents (select cytokines/growth factors) that could impact on its expression might not only affect immune cell profiles in a host but could potentially also limit apoptotic activities in (non-)immune cells in that host. In the context of cancer (immuno)therapy, in particular, when cord blood is used an important source in stem cell transplantation in leukemia patients, such down-regulating changes in c-Rel levels could be counter-productive. ARTICLE HISTORY

Characterization of gene regulatory networks underlying key properties in human hematopoietic stem cell ontogeny

“…We identified highly co-related modules(M1-3) that are highly active in UCB- and PB-HSPCs and regulate lymphoid and immune function. Several TFs in this module have been shown to promote HSC function or lymphoid lineage specification such as FOS, REL, KLF2 and HOXA9 (Yaseen et al 1994 ; Fallahi et al 2017 ; Hart et al 2012 ; Ramos-Mejía et al 2014 ). These data indicated the developmental changes and key properties in HSC ontogeny are being intrinsically controlled by the specific GRNs and key TFs.…”

Expression of nuclear factor kappa B components in the ovine maternal liver in early pregnancy periods

“…In this study, early pregnancy inhibited the expression of c-Rel mRNA and protein in the maternal liver, but there was an increase from Day 13 to 25 of pregnancy. The c-Rel subunit is a unique member of NF-κB family and has an essential role in B, T, and NK cell differentiation (Fallahi et al, 2017). There is a low level of c-Rel subunit in myometrium, which is helpful for pregnancy maintenance in humans (Chapman et al, 2004).…”