Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response.
Bacterial infection triggers host inflammation through the activation of immune cells, leading to the elimination of bacteria. However, the regulatory mechanisms of the host inflammatory response remain unknown. Here we report that a subset of potent tolerogenic dendritic cells (DCs), regulatory DCs (DC(regs)), control the systemic inflammatory response. Unlike normal DCs, which produced proinflammatory cytokines in response to bacterial lipopolysaccharide (LPS), DC(regs) produced fewer proinflammatory cytokines and instead preferentially produced interleukin-10 (IL-10), and these events involved the expression of IkappaBNS and Bcl-3 as well as cyclic AMP (cAMP)-mediated activation of protein kinase A (PKA). In addition, DC(regs) not only suppressed LPS-induced production of proinflammatory cytokines in macrophages, but also reduced their serum levels in mice. Furthermore, DC(regs) protected mice against the lethality induced by experimental endotoxemia and bacterial peritonitis. The inhibitory effect of DC(regs) against inflammatory responses involved the production of IL-10. On the other hand, naturally existing tolerogenic DC subsets producing IL-10, CD11c(low)CD45RB(high) DCs, also suppressed LPS-induced host inflammatory responses. Thus, a subset of tolerogenic DCs act as potential regulators of the host inflammatory response, and they might have preventive and therapeutic potential for the treatment of systemic as well as local inflammatory diseases.
Fujita
Shigeharu
S
Laboratory for Dendritic Cell Immunobiology, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Kanagawa 230-0045 Japan.
Seino
Ken-ichiro
K
Sato
Kaori
K
Sato
Yumiko
Y
Eizumi
Kawori
K
Yamashita
Naohide
N
Taniguchi
Masaru
M
Sato
Katsuaki
K
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000145:classification* / Q000276:immunology*; D019446:Endotoxemia / Q000150:complications / Q000276:immunology; D004927:Escherichia coli Infections / Q000150:complications / Q000276:immunology; D007108:Immune Tolerance; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010538:Peritonitis / Q000150:complications / Q000276:immunology; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control
D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016753:Interleukin-10