title: Independent signal transduction pathways for IL-1 and TNF in LPS-tolerant macrophages.
abstract: Macrophages rendered "tolerant" by pretreatment with low-dose endotoxin (LPSp) release less TNF and more IL-1 in response to a second activating endotoxin exposure (LPSa). We hypothesized that LPSp pretreatment alters signal transduction pathways for TNF and IL-1 independently. The effect of pretreatment with LPSp alone was compared to pretreatment with LPSp plus defined second-messenger pathway agonists or antagonists. Murine peritoneal macrophages were pretreated in vitro for 4 hr with LPSp or PMA or LPSp plus protein kinase C inhibitor (PKCi) or 8-bromo-cAMP. Cells were then washed and cultured with medium alone for 20 hr. Macrophages were also pretreated with LPSp plus indomethacin for the total 24-hr pretreatment interval. Cells were then stimulated for 24 hr with LPSa, after which supernatant TNF and IL-1 were measured by bioassay. In the absence of LPSp, mediators were increased by LPSa in a dose-dependent manner. LPSp pretreatment inhibited TNF and augmented IL-1 in response to LPSa. Pretreatment with PMA partially reproduced LPSp pretreatment. Pretreatment with PKCi alone increased both TNF and IL-1 release by LPSa. The combination of LPSp plus PKCi pretreatment further enhanced IL-1 release without affecting TNF inhibition. The addition of indomethacin had a similar effect. The combination of LPSp plus 8-bromo-cAMP blocked the augmentation of IL-1 without changing TNF inhibition. Macrophage endotoxin tolerance following LPSp pretreatment alters LPSa-triggered TNF and IL-1 release by independent signal transduction pathways.
authors.affiliation: Department of Surgery, Hennepin County Medical Center, University of Minnesota, Minneapolis 55415, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Seatter
authors.forename: L
authors.initials: L
authors.lastname: Clair
authors.forename: T
authors.initials: T
authors.lastname: Bennett
authors.forename: M
authors.initials: M
authors.lastname: Bubrick
authors.forename: M A
authors.initials: MA
authors.lastname: West
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011493:Protein Kinase C / Q000502:physiology; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D015124:8-Bromo Cyclic Adenosine Monophosphate; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin