Selective inhibition of NF-kappaB in dendritic cells by the NEMO-binding domain peptide blocks maturation and prevents T cell proliferation and polarization.
Dendritic cells (DC) are the only antigen-presenting cells for naive T cells and, therefore, they are crucial players in the initiation of immune responses. Because DC maturation and cytokine production are NF-kappaB dependent, we hypothesized that blocking NF-kappaB activity in DC by selectively targeting the inhibitor of kappaB (IkappaB) kinase (IKK) complex using the novel NF-kappaB inhibitor NEMO-binding domain (NBD) peptide could inhibit DC maturation and other functional characteristics, resulting in modulation of the immune response. We used human monocyte-derived DC to test the biological effects of the NBD peptide in vitro. NF-kappaB inhibition by the NBD peptide resulted in blockade of IKK-mediated IkappaBalpha phosphorylation and subsequent nuclear translocation and DNA binding of NF-kappaB p65 in DC. In addition, IL-6, IL-12, and TNF-alpha production was dose-dependently blocked and NBD peptide treatment also led to a strong reduction of LPS-induced maturation. Functional analysis of these DC showed marked inhibition of T cell proliferation in the allogeneic mixed lymphocyte reaction, accompanied by less Th1 and Th2 polarization. The current study reveals for the first time the unique properties of this novel, highly specific NF-kappaB inhibitor in DC. Also, these data indicate that the NBD peptide could be used as an elegant tool in DC based immunotherapy for unwanted cellular immune responses.
Tas
Sander W
SW
Division of Clinical Immunology and Rheumatology, AMC/University of Amsterdam, Amsterdam, The Netherlands.
de Jong
Esther C
EC
Hajji
Najat
N
May
Michael J
MJ
Ghosh
Sankar
S
Vervoordeldonk
Margriet J
MJ
Tak
Paul P
PP
D002454:Cell Differentiation / Q000276:immunology*; D002455:Cell Division / Q000276:immunology*; D004247:DNA / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation
D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; C467063:NBD peptide, mouse; D016328:NF-kappa B; D010455:Peptides; D004247:DNA