Impaired function of dendritic cells deficient in angiotensin II type 1 receptors.
Dendritic cells (DC) are highly specialized antigen-presenting cells with a unique ability to activate resting T lymphocytes and initiate primary immune responses. Angiotensin II (AII) is involved in key events of the inflammatory response. Because our previous work implicated an effect of AII on differentiation and function of murine and human DC, we investigated the impact of AII type 1 receptor (AT(1)) deficiency on the phenotypical and functional properties of mouse DC in vitro and in vivo. Bone marrow (BM) cells isolated from mice lacking AII subtype 1a receptor (AT(1a)), AII subtype 1b receptor (AT(1b)), or both receptor isoforms and control littermates [wild type (WT)] were cultured for 7 days in the presence of recombinant mouse granulocyte/macrophage colony-stimulating factor to generate myeloid DC in vitro. Generation of CD11c(+) cells was less efficient in both AT(1a)- and AT(1b)-deficient BM cells than in WT BM cell cultures. Moreover, DC generated from AT(1)-deficient progenitors showed lower levels of expression of major histocompatibility complex II (MHC-II) and CD11c (p < 0.01) and a marked reduction in their allostimulatory activity (p < 0.01 or 0.001). Although AT(1)-deficient DC released comparable levels of interleukin (IL)-10 and IL-12p70 to WT DC, they produced significantly lower levels of tumor necrosis factor alpha (TNF-alpha) (p < 0.05). Remarkably, CD11c(+) cells isolated from the spleen of AT(1) knockout mice challenged with lipopolysaccharide in vivo up-regulated MHC-II, CD40, and CD80 as did WT, but released significantly lower levels of TNF-alpha (p < 0.01). These data provide clear evidence that AT(1) controls differentiation and functionality of DC and thus may have a crucial impact on inflammatory processes where local angiotensinergic systems are known to be activated.
Laboratory of Immunology, Institute of Hematologic Research, National Academy of Medicine, Buenos Aires, Argentina.
Karen
K
Nahmod
Ciara
C
Gentilini
Monica
M
Vermeulen
Lutz
L
Uharek
Yong
Y
Wang
Jialin
J
Zhang
Heinz-Peter
HP
Schultheiss
Jorge
J
Geffner
Thomas
T
Walther
D000818:Animals; D015153:Blotting, Western; D039521:CD11c Antigen / Q000378:metabolism; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000502:physiology* / Q000648:ultrastructure; D004705:Endocytosis; D005434:Flow Cytometry; D005802:Genes, MHC Class II / Q000235:genetics; D005838:Genotype; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D039521:CD11c Antigen; D016207:Cytokines; D008070:Lipopolysaccharides; D044140:Receptor, Angiotensin, Type 1