Deficient translocation of c‐Rel is associated with impaired Th1 cytokine production in T cells from atopic dermatitis patients

Abstract

Decreased production of T helper type 1 (Th1) cytokines, such as interferon-gamma (IFN-gamma) or interleukin-2 (IL-2), is a hallmark of atopic diseases. While accessory signals from antigen-presenting cells may be missing, T cells themselves may be suppressed in their ability to produce substantial amounts of Th1 cytokines. We show, in this study, that T cell receptor (TCR)-activated T cells from atopic dermatitis (AD) patients proliferate less than control T cells and produce lower amounts of IFN-gamma and IL-2, but comparable amounts of IL-4. Because mice lacking the nuclear factor kappa B (NF-kappaB) transcription factors - p65 or c-Rel - show reduced Th1, but undisturbed Th2 responses, we investigated the role of c-Rel and p65 for Th1 cytokine production in T cells from healthy and severe AD patients. TCR-activated primary T cells from healthy donors treated with c-Rel antisense oligonucleotides produced lower levels of IL-2 and IFN-gamma and proliferated less efficiently than the corresponding control T cells. Moreover, transfection of primary T cells with c-Rel or p65 enhanced proliferation and production of IL-2 and IFN-gamma. Nuclear extracts of activated primary T cells from AD donors bound weakly to NF-kappaB-specific oligonucleotides, compared to extracts from healthy control T cells. Western blotting studies revealed that nuclear, but not cytosolic, extracts from T cells of AD patients lacked significant amounts of c-Rel and p65. T cell clones derived from AD patients failed to sufficiently translocate c-Rel and p65 into the nucleus following activation. Thus, impaired nuclear translocation of c-Rel and p65 may determine an impaired Th1 cytokine response in AD.

Herpes Simplex Virus Remodels T-Cell Receptor Signaling, Resulting in p38-Dependent Selective Synthesis of Interleukin-10

“…In HSV-infected T cells, we have demonstrated a distinct pattern characterized by p38 and JNK activation and NF-B inhibition. HSV-induced NF-B inhibition may play a role in inhibition of Th1 cytokine synthesis, as NF-B activation has been associated with increased Th1 cytokine synthesis (10). While epithelial cells and antigenpresenting cells may be a source of IL-10 in HSV infection, ours is the first report demonstrating that HSV-infected T cells may be an additional, important source of IL-10 produced during HSV infection.…”

Role of transcriptional factors Sp1, c-Rel, and c-Jun in LPS-induced C/EBPδ gene expression of mouse macrophages

“…In macrophages, c-Rel is more potent than p65 in the induction of IL-12 p40 gene [44], while it also increases IL-12 p35 gene expression in CD8(+) dendritic cells [45]. The location of c-Rel is also important for targeting the gene expression, for example, defective translocation of cRel is associated with impaired Th1 cytokine production in T cells from atopic dermatitis patients [46]. Calmodulin binds to c-Rel released from I kappa B, and thus inhibits nuclear import of c-Rel and prevents c-Rel acting on its target genes [47].…”

Nuclear Factor κB Activity is Increased in Peripheral Blood Mononuclear Cells of Children Affected by Atopic and Non-Atopic Eczema

“…Nevertheless, no study has been devoted to investigate NF-KB-DNA binding activity in children affected by eczema, and only one report has been published on adult patients on this issue (21 ).…”

“…In particular, the over-expression of IL-12 contributes to the promotion of the switch to the Th I cytokine profile typical of chronic eczema (12). Although NF-KB has been hitherto considered as mediator of acute inflammatory responses, it has been shown to be persistently activated also in chronic inflammatory conditions such as inflammatory arthritis (13), inflammatory bowel diseases (14), atherosclerosis (15), asthma (16)(17), and, more recently, also in psoriasis (18-20) and eczema (21).…”