Rel-deficient T cells exhibit defects in production of interleukin 3 and granulocyte-macrophage colony-stimulating factor.

Abstract

The c-rel protooncogene encodes a subunit of the NF-KB-like family of transcription factors. Mice lacking Rel are defective in mitogenic activation of B and T lymphocytes and display impaired humoral immunity. In an attempt to identify changes in gene expression that accompany the T-cell stimulation defects associated with the loss of Rel, we have examined the expression of cell surface activation markers and cytokine production in mitogen-stimulated Rel-/-T cells. The expression of cell surface markers including the interleukin 2 receptor a (IL-2Ra) chain (CD25), CD69 and L-selectin (CD62) is normal in mitogen-activated Rel-/-T cells, but cytokine production is impaired. In Rel-/-splenic T cell cultures stimulated with phorbol 12-myristate 13-acetate and ionomycin, the levels of IL-3, IL-5, granulocytemacrophage colony-stimulating factor (GM-CSF), tumor necrosis factor a (TNF-a), and y interferon (IFN-y) (12,(17)(18)(19). Rel/ NF-KB has also been implicated in transcriptional regulation of other cytokine genes expressed in activated T cells (5, 18). The promoters of the genes encoding IL-3, IL-5, tumor necrosis factor a (TNF-a), granulocyte-macrophage colonystimulating factor (GM-CSF) and y interferon (IFN-3y)

ETS1, NFκB and AP1 synergistically transactivate the human GM – CSF promoter

“…The data presented here clearly show that both NFkB and AP1 binding activities remain high in cells treated with PMA/ionomycin for 4 h, a time point at which we estimated the GM ± CSF promoter was most active (data not shown). Gene disruption of members of the NFkB/Rel family in mice produces T cell defects; disrupted p50 results in T cells with decreased ability to proliferate in response to activation signals ; p65 inactivation is an embryonic lethal mutation, but does cause defects in GM ± CSF induction in cell lines (Beg et al, 1995b); and c-rel disruption results both in defects in T cell proliferation (Kontgen et al, 1995) and GM ± CSF transcription (Gerondakis et al, 1996). Inactivation of IkB results in enhanced granulopoiesis (Beg et al, 1995a), possibly caused by increased or constitutive expression of cytokines such as GM ± CSF.…”

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…Despite its ubiquitous expression, the absence of p105 is tolerated during embryonic development and is compatible with neonatal and adult viability (Sha et al, 1995). In addition to a mild learning deficit (Meffert and Baltimore, 2005), loss of NF-kB p50/p105 function is associated with defects in stress responses, Hu et al (1999), Li et al (1999a), Takeda Grumont et al (1998Grumont et al ( , 1999, Cheng et al (2003), Pohl et al (2002) T cells: defects in CD4 and CD8 T-cell responses, Th1 development and cytokine production (IL-2 and GM-CSF) in CD4 + T-cell responses Hilliard et al (2002), Lamhamedi-Cherradi et al (2003), Mason et al (2004), Gerondakis et al (1996), Rao et al (2003) Horwitz et al (1997) rela À/À c-rel À/À Yes (BE13) Multiple hemopoietic defects. Radiation chimeras exhibit nucleated erythrocytes, reduced number of B cells, systemic expansion of granulocytes and a reduction in monocytes Grossmann et al (1999Grossmann et al ( , 2000 T cells exhibit a cell-cycle block early in G1 resulting from a failure to undergo c-Myc-dependent growth Grumont et al (2004) rela À/À c-rel À/ À tnf À/À Neonatal E18 embryos exhibit multiple epidermal defects that include a failure to form specific hair types, disorganized basal Gugasyan et al (2004) Knockout and transgenic models for NF-jB pathway S Gerondakis et al plus impaired innate and adaptive immune function.…”

“…In CD4 þ T cells, c-Rel is required for proinflammatory cytokine priming of immune responsiveness that leads to faster and greater production of IFNg and IL-2 by naı¨ve but not effector T cells (Banerjee et al, 2005). During CD4 þ T-cell activation, c-Rel is required for the efficient production of IL-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (Gerondakis et al, 1996), which in the case of IL-2 involves c-Rel directly regulating IL-2 transcription by controlling chromatin remodelling across the IL-2 promoter (Rao et al, 2003;Chen et al, 2005).…”

A chicken c-Rel-estrogen receptor chimeric protein shows conditional nuclear localization, DNA binding, transformation and transcriptional activation

“…Most members of the Rel/NF-kB family have been implicated in the transcriptional regulation of genes involved in immunoregulatory processes, cell growth, and di erentiation (for a recent review see Baeuerle and Baltimore, 1996). Consistent with these ®ndings, c-Rel has been implicated in the transcriptional regulation of genes encoding cell adhesion molecules, growth factors such as GM-CSF, interleukin-2 and 3, and their receptors (Kontgen et al, 1995;Gerondakis et al, 1996).…”

“…Recent studies indicate that c-Rel plays a critical role in regulation of B lymphocyte proliferation and T-cell activation (Kontgen et al, 1995, Gerondakis et al, 1996. Structurally, c-Rel belongs to a larger family of transcription factors, the Rel/NF-kB family, which also includes RelA, RelB, NF-kB1, NF-kB2, Dorsal, Dif, and Relish.…”