{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:33:35Z","timestamp":1792521215439,"version":"4.5.0"},"reference-count":89,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2009,7,1]],"date-time":"2009-07-01T00:00:00Z","timestamp":1246406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In vitro and in vivo experiments in mice have shown that exposure of cells to the TLR4 ligand LPS induces tolerance toward a second exposure to LPS and induces cross-tolerance to certain other TLR ligands. Recently, we found that LPS tolerance in experimental human endotoxemia and Gram-negative sepsis is associated with elevated levels of IL-1R-associated kinase M, an intracellular negative regulator of MyD88-dependent TLR signaling. In the present study, we investigated whether in vivo exposure of humans to LPS induces tolerance in circulating leukocytes to other TLR agonists that rely either on MyD88- dependent or on MyD88-independent signaling. Analysis of TNF, IL-1\u03b2, IL-6, and IL-10 levels in whole blood demonstrated that leukocytes were hyporesponsive to ex vivo LPS restimulation 3\u20138 h after i.v. LPS injection (4 ng\/kg). Reduced cytokine release during the same interval was also observed in whole blood further stimulated with MyD88-dependent ligands for TLR2, TLR5, and TLR7 or with whole bacteria. Strikingly, blood leukocytes were also tolerant to a ligand for TLR3, which signals solely through a MyD88-independent (Toll IL-1R domain-containing adaptor-inducing IFN-\u03b2 (TRIF)-dependent) pathway. The hyporesponsiveness of leukocytes to TLR3 ligation was associated with reduced rather than increased levels of the recently identified TRIF inhibitor SARM. Taken together, these data indicate that systemic LPS challenge of human volunteers induces cross-tolerance to multiple TLR ligands that signal in a MyD88-dependent or MyD88-independent manner and suggest that LPS exposure of human blood leukocytes may hamper the inflammatory response to various microbial components.<\/jats:p>","DOI":"10.4049\/jimmunol.0802189","type":"journal-article","created":{"date-parts":[[2009,6,19]],"date-time":"2009-06-19T17:04:08Z","timestamp":1245431048000},"page":"533-542","source":"Crossref","is-referenced-by-count":95,"title":["In Vivo Lipopolysaccharide Exposure of Human Blood Leukocytes Induces Cross-Tolerance to Multiple TLR Ligands"],"prefix":"10.1093","volume":"183","author":[{"given":"Alex F","family":"de Vos","sequence":"first","affiliation":[{"name":"Center of Infection and Immunity Amsterdam and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennie M","family":"Pater","sequence":"additional","affiliation":[{"name":"Center of Infection and Immunity Amsterdam and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra S","family":"van den Pangaart","sequence":"additional","affiliation":[{"name":"Center of Infection and Immunity Amsterdam and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn D","family":"de Kruif","sequence":"additional","affiliation":[{"name":"Center of Infection and Immunity Amsterdam and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelis","family":"van 't Veer","sequence":"additional","affiliation":[{"name":"Center of Infection and Immunity Amsterdam and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"van der Poll","sequence":"additional","affiliation":[{"name":"Center of Infection and Immunity Amsterdam and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,7,1]]},"reference":[{"key":"2026012811285119000_R1","first-page":"539","article-title":"Granulocyte function in experimental human endotoxemia.","volume-title":"Blood","year":"1976"},{"key":"2026012811285119000_R2","first-page":"1264","article-title":"Reduced ex vivo chemokine production by polymorphonuclear cells after in vivo exposure of normal humans to endotoxin.","volume-title":"J. Infect. Dis.","year":"2000"},{"key":"2026012811285119000_R3","first-page":"1014","article-title":"Reduced Th1, but not Th2, cytokine production by lymphocytes after in vivo exposure of healthy subjects to endotoxin.","volume-title":"Infect. Immun.","year":"2000"},{"key":"2026012811285119000_R4","first-page":"1637","article-title":"Intravenous endotoxin suppresses the cytokine response of peripheral blood mononuclear cells of healthy humans.","volume-title":"J. Immunol.","year":"1993"},{"key":"2026012811285119000_R5","first-page":"1356","article-title":"Changes in endotoxin-induced cytokine production by whole blood after in vivo exposure of normal humans to endotoxin.","volume-title":"J. Infect. Dis.","year":"1996"},{"key":"2026012811285119000_R6","first-page":"S64","article-title":"Endotoxin tolerance: A review.","volume-title":"Crit. Care Med.","year":"2002"},{"key":"2026012811285119000_R7","first-page":"1747","article-title":"Dysregulation of in vitro cytokine production by monocytes during sepsis.","volume-title":"J. Clin. Invest.","year":"1991"},{"key":"2026012811285119000_R8","first-page":"1341","article-title":"Downregulation of proinflammatory cytokine release in whole blood from septic patients.","volume-title":"Blood","year":"1995"},{"key":"2026012811285119000_R9","first-page":"853","article-title":"Tolerance to endotoxin-induced expression of the interleukin-1 \u03b2 gene in blood neutrophils of humans with the sepsis syndrome.","volume-title":"J. Clin. Invest.","year":"1993"},{"key":"2026012811285119000_R10","first-page":"569","article-title":"Immunosuppression associated with interleukin-1R-associated-kinase-M upregulation predicts mortality in Gram-negative sepsis (melioidosis).","volume-title":"Crit. Care Med.","year":"2009"},{"key":"2026012811285119000_R11","first-page":"85","article-title":"Immunodepression in sepsis and SIRS assessed by ex vivo cytokine production is not a generalized phenomenon: a review.","volume-title":"J. Endotoxin Res.","year":"2001"},{"key":"2026012811285119000_R12","first-page":"12","article-title":"Proinflammatory cytokine gene expression in whole blood from patients undergoing coronary artery bypass surgery and its modulation by pentoxifylline.","volume-title":"Shock","year":"1998"},{"key":"2026012811285119000_R13","first-page":"313","article-title":"The extent of traumatic damage determines a graded depression of the endotoxin responsiveness of peripheral blood mononuclear cells from patients with blunt injuries.","volume-title":"Crit. Care Med.","year":"1999"},{"key":"2026012811285119000_R14","first-page":"158","article-title":"Toll-like receptor-mediated tumor necrosis factor and interleukin-10 production differ during systemic inflammation.","volume-title":"Am. J. Respir. Crit. Care Med.","year":"2003"},{"key":"2026012811285119000_R15","first-page":"7110","article-title":"Induction of IRAK-M is associated with lipopolysaccharide tolerance in a human endotoxemia model.","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012811285119000_R16","first-page":"499","article-title":"Toll-like receptor signalling.","volume-title":"Nat. Rev. Immunol.","year":"2004"},{"key":"2026012811285119000_R17","first-page":"460","article-title":"Signaling to NF-\u03baB by Toll-like receptors.","volume-title":"Trends Mol. Med.","year":"2007"},{"key":"2026012811285119000_R18","first-page":"446","article-title":"Negative regulation of Toll-like receptor-mediated immune responses.","volume-title":"Nat. Rev. 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Autoimmun.","year":"2003"},{"key":"2026012811285119000_R60","first-page":"465","article-title":"Human TLR-7-, -8-, and -9-mediated induction of IFN-\u03b1\/\u03b2 and -\u03bb is IRAK-4 dependent and redundant for protective immunity to viruses.","volume-title":"Immunity","year":"2005"},{"key":"2026012811285119000_R61","first-page":"565","article-title":"CD14 is required for MyD88-independent LPS signaling.","volume-title":"Nat. Immunol.","year":"2005"},{"key":"2026012811285119000_R62","first-page":"348","article-title":"TRIM-ing down Tolls.","volume-title":"Nat. Immunol.","year":"2008"},{"key":"2026012811285119000_R63","first-page":"1835","article-title":"The nature of the principal type 1 interferon-producing cells in human blood.","volume-title":"Science","year":"1999"},{"key":"2026012811285119000_R64","first-page":"24","article-title":"Innate immune functions of plasmacytoid dendritic cells.","volume-title":"Curr. Opin. Immunol.","year":"2007"},{"key":"2026012811285119000_R65","first-page":"2423","article-title":"Specialization, kinetics, and repertoire of type 1 interferon responses by human plasmacytoid predendritic cells.","volume-title":"Blood","year":"2006"},{"key":"2026012811285119000_R66","first-page":"86","article-title":"A whole blood assay to assess peripheral blood dendritic cell function in response to Toll-like receptor stimulation.","volume-title":"J. Immunol. Methods","year":"2006"},{"key":"2026012811285119000_R67","first-page":"1507","article-title":"Interferon-\u03b1 and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets.","volume-title":"J. Exp. Med.","year":"2002"},{"key":"2026012811285119000_R68","first-page":"2291","article-title":"Distinct CpG DNA and polyinosinic-polycytidylic acid double-stranded RNA, respectively, stimulate CD11c\u2212 type 2 dendritic cell precursors and CD11c+ dendritic cells to produce type I IFN.","volume-title":"J. Immunol.","year":"2001"},{"key":"2026012811285119000_R69","first-page":"3128","article-title":"Potent suppression of IL-12 production from monocytes and dendritic cells during endotoxin tolerance.","volume-title":"Eur. J. Immunol.","year":"1998"},{"key":"2026012811285119000_R70","first-page":"236","article-title":"Endotoxin inducible transcription is repressed in endotoxin tolerant cells.","volume-title":"Shock","year":"2000"},{"key":"2026012811285119000_R71","first-page":"972","article-title":"Gene-specific control of inflammation by TLR-induced chromatin modifications.","volume-title":"Nature","year":"2007"},{"key":"2026012811285119000_R72","first-page":"461","article-title":"Endotoxin tolerance disrupts chromatin remodeling and NF-\u03baB transactivation at the IL-1\u03b2 promoter.","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012811285119000_R73","first-page":"369","article-title":"TRIM30\u03b1 negatively regulates TLR-mediated NF-\u03baB activation by targeting TAB2 and TAB3 for degradation.","volume-title":"Nat. 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