PMID- 30037846 OWN - NLM STAT- MEDLINE DCOM- 20190701 LR - 20190716 IS - 1550-6606 (Electronic) IS - 0022-1767 (Linking) VI - 201 IP - 5 DP - 2018 Sep 1 TI - Toll-like Receptor 4-Induced Glycolytic Burst in Human Monocyte-Derived Dendritic Cells Results from p38-Dependent Stabilization of HIF-1alpha and Increased Hexokinase II Expression. PG - 1510-1521 LID - 10.4049/jimmunol.1701522 [doi] AB - Cell metabolism now appears as an essential regulator of immune cells activation. In particular, TLR stimulation triggers metabolic reprogramming of dendritic cells (DCs) with an increased glycolytic flux, whereas inhibition of glycolysis alters their functional activation. The molecular mechanisms involved in the control of glycolysis upon TLR stimulation are poorly understood for human DCs. TLR4 activation of human monocyte-derived DCs (MoDCs) stimulated glycolysis with an increased glucose consumption and lactate production. Global hexokinase (HK) activity, controlling the initial rate-limiting step of glycolysis, was also increased. TLR4-induced glycolytic burst correlated with a differential modulation of HK isoenzymes. LPS strongly enhanced the expression of HK2, whereas HK3 was reduced, HK1 remained unchanged, and HK4 was not expressed. Expression of the other rate-limiting glycolytic enzymes was not significantly increased. Exploring the signaling pathways involved in LPS-induced glycolysis with various specific inhibitors, we observed that only the inhibitors of p38-MAPK (SB203580) and of HIF-1alpha DNA binding (echinomycin) reduced both the glycolytic activity and production of cytokines triggered by TLR4 stimulation. In addition, LPS-induced HK2 expression required p38-MAPK-dependent HIF-1alpha accumulation and transcriptional activity. TLR1/2 and TLR2/6 stimulation increased glucose consumption by MoDCs through alternate mechanisms that are independent of p38-MAPK activation. TBK1 contributed to glycolysis regulation when DCs were stimulated via TLR2/6. Therefore, our results indicate that TLR4-dependent upregulation of glycolysis in human MoDCs involves a p38-MAPK-dependent HIF-1alpha accumulation, leading to an increased HK activity supported by enhanced HK2 expression. CI - Copyright (c) 2018 by The American Association of Immunologists, Inc. FAU - Perrin-Cocon, Laure AU - Perrin-Cocon L AUID- ORCID: 0000-0003-0501-6733 AD - Centre International de Recherche en Infectiologie, Biologie Cellulaire des Infections Virales, INSERM, U1111, Universite Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Superieure de Lyon, Hospices Civils de Lyon, Universite de Lyon, Lyon, France; and laure.perrin@inserm.fr vincent.lotteau@inserm.fr. FAU - Aublin-Gex, Anne AU - Aublin-Gex A AD - Centre International de Recherche en Infectiologie, Biologie Cellulaire des Infections Virales, INSERM, U1111, Universite Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Superieure de Lyon, Hospices Civils de Lyon, Universite de Lyon, Lyon, France; and. FAU - Diaz, Olivier AU - Diaz O AD - Centre International de Recherche en Infectiologie, Biologie Cellulaire des Infections Virales, INSERM, U1111, Universite Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Superieure de Lyon, Hospices Civils de Lyon, Universite de Lyon, Lyon, France; and. FAU - Ramiere, Christophe AU - Ramiere C AUID- ORCID: 0000-0002-1981-7155 AD - Centre International de Recherche en Infectiologie, Biologie Cellulaire des Infections Virales, INSERM, U1111, Universite Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Superieure de Lyon, Hospices Civils de Lyon, Universite de Lyon, Lyon, France; and. FAU - Peri, Francesco AU - Peri F AD - Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milano, Italy. FAU - Andre, Patrice AU - Andre P AUID- ORCID: 0000-0002-5834-7395 AD - Centre International de Recherche en Infectiologie, Biologie Cellulaire des Infections Virales, INSERM, U1111, Universite Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Superieure de Lyon, Hospices Civils de Lyon, Universite de Lyon, Lyon, France; and. FAU - Lotteau, Vincent AU - Lotteau V AD - Centre International de Recherche en Infectiologie, Biologie Cellulaire des Infections Virales, INSERM, U1111, Universite Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Superieure de Lyon, Hospices Civils de Lyon, Universite de Lyon, Lyon, France; and laure.perrin@inserm.fr vincent.lotteau@inserm.fr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180723 PL - United States TA - J Immunol JT - Journal of immunology (Baltimore, Md. : 1950) JID - 2985117R RN - 0 (HIF1A protein, human) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Lipopolysaccharides) RN - 0 (TLR4 protein, human) RN - 0 (Toll-Like Receptor 4) RN - 0 (lipopolysaccharide, Escherichia coli O111 B4) RN - EC 2.7.1.1 (HK2 protein, human) RN - EC 2.7.1.1 (Hexokinase) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) SB - IM MH - Cells, Cultured MH - Dendritic Cells/*immunology/pathology MH - Gene Expression Regulation, Enzymologic/drug effects/*immunology MH - Hexokinase/*immunology MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/*immunology MH - Lipopolysaccharides/toxicity MH - Monocytes/*immunology/pathology MH - Protein Stability MH - Toll-Like Receptor 4/agonists/*immunology MH - p38 Mitogen-Activated Protein Kinases/*immunology EDAT- 2018/07/25 06:00 MHDA- 2019/07/02 06:00 CRDT- 2018/07/25 06:00 PHST- 2017/11/10 00:00 [received] PHST- 2018/07/03 00:00 [accepted] PHST- 2018/07/25 06:00 [pubmed] PHST- 2019/07/02 06:00 [medline] PHST- 2018/07/25 06:00 [entrez] AID - jimmunol.1701522 [pii] AID - 10.4049/jimmunol.1701522 [doi] PST - ppublish SO - J Immunol. 2018 Sep 1;201(5):1510-1521. doi: 10.4049/jimmunol.1701522. Epub 2018 Jul 23.