Abstract
Ligation of CD40 on dendritic cells (DCs) induces early production of inflammatory mediators via canonical NF-kappaB signaling, as well as late expression of the anti-inflammatory enzyme indoleamine 2,3-dioxygenase (IDO) via unknown signal transduction. By selective blocking of either the canonical NF-kappaB pathway using the NEMO-binding domain peptide or the noncanonical NF-kappaB pathway by small interfering RNA, we demonstrate that IDO expression requires noncanonical NF-kappaB signaling. Also, noncanonical NF-kappaB signaling down-regulates proinflammatory cytokine production in DCs. In addition, selective activation of the noncanonical NF-kappaB pathway results in noninflammatory DCs that suppress T-cell activation and promote the development of T cells with regulatory properties. These findings reveal an important role of the noncanonical NF-kappaB pathway in the regulation of immunity.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cells, Cultured
-
Cytokines / biosynthesis
-
Cytokines / immunology
-
Dendritic Cells / enzymology
-
Dendritic Cells / immunology*
-
Gene Expression Regulation, Enzymologic / drug effects
-
Gene Expression Regulation, Enzymologic / immunology*
-
Humans
-
I-kappa B Kinase / immunology
-
I-kappa B Kinase / metabolism
-
Indoleamine-Pyrrole 2,3,-Dioxygenase / biosynthesis
-
Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology*
-
Inflammation / immunology
-
Inflammation / metabolism
-
Lymphocyte Activation / drug effects
-
Lymphocyte Activation / immunology*
-
Mice
-
NF-kappa B / antagonists & inhibitors
-
NF-kappa B / immunology*
-
NF-kappa B / metabolism
-
Peptides / immunology
-
Peptides / metabolism
-
Peptides / pharmacology
-
Protein Binding / drug effects
-
Protein Binding / immunology
-
RNA, Small Interfering / immunology
-
RNA, Small Interfering / pharmacology
-
Signal Transduction / drug effects
-
Signal Transduction / immunology*
-
T-Lymphocytes / immunology*
-
T-Lymphocytes / metabolism
Substances
-
Cytokines
-
IKBKG protein, human
-
Indoleamine-Pyrrole 2,3,-Dioxygenase
-
NF-kappa B
-
Peptides
-
RNA, Small Interfering
-
I-kappa B Kinase