title: Endotoxin-adapted septic shock leukocytes selectively alter production of sIL-1RA and IL-1beta.
abstract: During septic shock, circulating levels of anti-inflammatory mediators are increased relative to those of pro-inflammatory. The reduced capacity of septic shock blood leukocytes in expressing pro-inflammatory genes in response to bacterial lipopolysaccharide endotoxin (LPS) may contribute to reductions in these mediators, but the reasons for persistent increases in circulating anti-inflammatory mediators are unknown. We determined whether septic shock leukocytes that have adapted to LPS induction of the IL-1beta gene could continue to express sIL-1RA in response to LPS. Septic shock whole-blood leukocytes and neutrophils (PMNs) selectively maintained production of sIL-1RA after treatment with LPS while limiting that of IL-1beta. Repressed transcription of IL-1beta and rapid decay of IL-1beta mRNA in septic shock neutrophils correlated with reductions in levels of IL-1beta after stimulation with LPS. Transcription of sIL-1RA mRNA was also suppressed, but the ability of LPS to stimulate events that lead to efficient translation of a stable sIL-1RA mRNA appeared responsible for maintaining sIL-1RA production. We conclude that LPS adaptation of septic shock leukocytes selectively influences signaling pathways that regulate transcription, mRNA processing, and translation, leading to changes in the balance of production of pro- and anti-inflammatory mediators.
authors.affiliation: Section on Infectious Diseases, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27104, USA.
authors.forename: L P
authors.initials: LP
authors.lastname: Mueller
authors.forename: B K
authors.initials: BK
authors.lastname: Yoza
authors.forename: K
authors.initials: K
authors.lastname: Neuhaus
authors.forename: C S
authors.initials: CS
authors.lastname: Loeser
authors.forename: S
authors.initials: S
authors.lastname: Cousart
authors.forename: M C
authors.initials: MC
authors.lastname: Chang
authors.forename: J W
authors.initials: JW
authors.lastname: Meredith
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: C E
authors.initials: CE
authors.lastname: McCall
mesh_terms: D000222:Adaptation, Physiological; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D016022:Case-Control Studies; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology*; D012795:Sialoglycoproteins / Q000096:biosynthesis*; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; C507763:IL1RN protein, human; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D012795:Sialoglycoproteins