PMID- 25278421 OWN - NLM STAT- MEDLINE DCOM- 20150805 LR - 20141216 IS - 1878-3279 (Electronic) IS - 0171-2985 (Linking) VI - 220 IP - 2 DP - 2015 Feb TI - LPS-conditioned dendritic cells confer endotoxin tolerance contingent on tryptophan catabolism. PG - 315-21 LID - S0171-2985(14)00178-8 [pii] LID - 10.1016/j.imbio.2014.09.017 [doi] AB - Dendritic cells (DCs) are specialized antigen-presenting cells with a bipolar nature. Depending on environmental factors, DCs will promote either inflammatory or anti-inflammatory effects. Lipopolysaccharide (LPS), a ligand of Toll-like receptor (TLR)4 and a most potent proinflammatory stimulus, is responsible for complex signaling events in different cell types, including DCs. LPS effects range from protective inflammation-capable of counteracting growth and dissemination of gram-negative bacteria - to hyperacute detrimental responses, as it occurs in endotoxic shock. Consistent with the plasticity of TLR4 signaling, a low dosage of LPS will induce a regulatory response capable of protecting mice against a subsequent, otherwise lethal challenge ('endotoxin tolerance'). By examining CD11c(+) DCs ('conventional' DCs, or cDCs), we investigated whether DC flexibility in promoting either inflammation or tolerance can be differentially affected by single vs. repeated exposure to LPS in vitro. cDCs stimulated twice with LPS expressed high levels of indoleamine 2,3-dioxygenase 1 (IDO1) - one of the most effective mediator of anti-inflammatory activity by DCs - and of TGF-beta, an immunoregulatory cytokine capable of upregulating IDO1 expression and function. In contrast, a single exposure to LPS failed to upregulate IDO1, and it was instead associated with high-level production of IL-6, a cytokine that promotes inflammation and proteolysis of IDO1. When adoptively transferred in vivo, only cDCs on double endotoxin exposure greatly improved the outcome of an otherwise lethal LPS challenge. The protective effect required that the transferred cDCs be fully competent for IDO1 and the host for TGF-beta production. Thus cDCs, conditioned by LPS in vitro to mimic an endotoxin-tolerant state, can protect recipients from endotoxic shock, pointing to adoptive transfer of tolerance as a new option for controlling potentially harmful responses to TLR4 signaling. CI - Copyright (c) 2014 Elsevier GmbH. All rights reserved. FAU - Fallarino, Francesca AU - Fallarino F AD - Department of Experimental Medicine, University of Perugia, Perugia, Italy. Electronic address: fllfnc@tin.it. FAU - Pallotta, Maria T AU - Pallotta MT AD - Department of Experimental Medicine, University of Perugia, Perugia, Italy. FAU - Matino, Davide AU - Matino D AD - Department of Experimental Medicine, University of Perugia, Perugia, Italy. FAU - Gargaro, Marco AU - Gargaro M AD - Department of Experimental Medicine, University of Perugia, Perugia, Italy. FAU - Orabona, Ciriana AU - Orabona C AD - Department of Experimental Medicine, University of Perugia, Perugia, Italy. FAU - Vacca, Carmine AU - Vacca C AD - Department of Experimental Medicine, University of Perugia, Perugia, Italy. FAU - Mondanelli, Giada AU - Mondanelli G AD - Department of Experimental Medicine, University of Perugia, Perugia, Italy. FAU - Allegrucci, Massimo AU - Allegrucci M AD - Department of Experimental Medicine, University of Perugia, Perugia, Italy. FAU - Boon, Louis AU - Boon L AD - Bioceros, Utrecht, The Netherlands. FAU - Romani, Rita AU - Romani R AD - Department of Experimental Medicine, University of Perugia, Perugia, Italy; Bioceros, Utrecht, The Netherlands. FAU - Talesa, Vincenzo N AU - Talesa VN AD - Department of Experimental Medicine, University of Perugia, Perugia, Italy; Bioceros, Utrecht, The Netherlands. FAU - Puccetti, Paolo AU - Puccetti P AD - Department of Experimental Medicine, University of Perugia, Perugia, Italy. FAU - Grohmann, Ursula AU - Grohmann U AD - Department of Experimental Medicine, University of Perugia, Perugia, Italy. Electronic address: ugrohmann@tin.it. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140928 PL - Netherlands TA - Immunobiology JT - Immunobiology JID - 8002742 RN - 0 (Cytokines) RN - 0 (Endotoxins) RN - 0 (IDO1 protein, mouse) RN - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase) RN - 0 (Inflammation Mediators) RN - 0 (Lipopolysaccharides) RN - 8DUH1N11BX (Tryptophan) SB - IM MH - Adoptive Transfer MH - Animals MH - Cytokines/biosynthesis MH - Dendritic Cells/*immunology/*metabolism MH - Disease Models, Animal MH - Endotoxins/*immunology MH - Gene Expression MH - *Immune Tolerance/genetics MH - Indoleamine-Pyrrole 2,3,-Dioxygenase/deficiency/genetics MH - Inflammation Mediators/metabolism MH - Lipopolysaccharides/*immunology MH - Lung/immunology/metabolism/pathology MH - Male MH - Mice MH - Mice, Knockout MH - Models, Biological MH - Shock, Septic/genetics/immunology/metabolism/mortality MH - Tryptophan/*metabolism OTO - NOTNLM OT - Adoptive transfer OT - Dendritic cells OT - Endotoxic shock OT - Endotoxin tolerance OT - IDO1 OT - Tryptophan catabolism EDAT- 2014/10/04 06:00 MHDA- 2015/08/06 06:00 CRDT- 2014/10/04 06:00 PHST- 2014/04/30 00:00 [received] PHST- 2014/08/20 00:00 [revised] PHST- 2014/09/15 00:00 [accepted] PHST- 2014/10/04 06:00 [entrez] PHST- 2014/10/04 06:00 [pubmed] PHST- 2015/08/06 06:00 [medline] AID - S0171-2985(14)00178-8 [pii] AID - 10.1016/j.imbio.2014.09.017 [doi] PST - ppublish SO - Immunobiology. 2015 Feb;220(2):315-21. doi: 10.1016/j.imbio.2014.09.017. Epub 2014 Sep 28.