title: LPS pretreatment reprograms macrophage LPS-stimulated TNF and IL-1 release without protein tyrosine kinase activation.
abstract: Pretreatment of macrophages with low-dose endotoxin (LPSp) profoundly alters cytokine release in response to subsequent LPSa activation. These qualitative and quantitative alterations in cytokine release have been termed macrophage reprogramming. Macrophage activation by LPS is thought to occur via a mechanism involving an early protein tyrosine kinase (PTK) phosphorylation step. PTK inhibition with genistein or herbimycin A blocks LPSa-stimulated secretion of tumor necrosis factor (TNF) and interleukin-1 (IL-1). In this study we investigated whether a PTK pathway participates in LPSp pretreatment reprogramming. We show that LPSp pretreatment inhibited TNF and augmented IL-1 release in response to subsequent LPSa stimulation. Blockade of PTK activation pathways during the interval when macrophages were exposed to LPSp prevented mitogen-activated protein kinase phosphorylation, as well as LPSp-stimulated release of TNF and IL-1, but did not block LPSp reprogramming effects. We conclude that LPSp pretreatment reprogramming of macrophage cytokine production does not require PTK activation.
authors.affiliation: Department of Surgery, Hennepin County Medical Center, University of Minnesota, Minneapolis 55415, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: West
authors.forename: T
authors.initials: T
authors.lastname: Bennet
authors.forename: S C
authors.initials: SC
authors.lastname: Seatter
authors.forename: L
authors.initials: L
authors.lastname: Clair
authors.forename: J
authors.initials: J
authors.lastname: Bellingham
mesh_terms: D000818:Animals; D016227:Benzoquinones; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D019833:Genistein; D007375:Interleukin-1 / Q000378:metabolism*; D007529:Isoflavones / Q000008:administration & dosage / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011809:Quinones / Q000008:administration & dosage / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D007375:Interleukin-1; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides; D011809:Quinones; D014409:Tumor Necrosis Factor-alpha; D017828:Rifabutin; C020754:herbimycin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1