Deficient translocation of c-Rel is associated with impaired Th1 cytokine production in T cells from atopic dermatitis patients.
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.
Dieckhoff
Karsten
K
Department of Dermatology, University Goettingen, Germany.
Graf
Philipp
P
Beinhauer
Brigitte
B
Schwaerzler
Christoph
C
Carballido
José M
JM
Neumann
Christine
C
Zachmann
Karolin
K
Jung
Thomas
T
D021581:Active Transport, Cell Nucleus / Q000276:immunology; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000097:blood / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism*; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D007376:Interleukin-2; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; C497593:RELB protein, human; D051996:Transcription Factor RelA; D014157:Transcription Factors; D051841:Transcription Factor RelB; D007371:Interferon-gamma; D004247:DNA