title: The role of interleukin-1beta in direct and toll-like receptor 4-mediated neutrophil activation and survival.
abstract: The regulation of systemic and local neutrophil activation is crucial to the clearance of infections and the successful resolution of inflammation without progress to tissue damage or disseminated inflammatory reactions. Using purified lipopolysaccharide (pLPS) and highly purified neutrophils, we have previously shown that Toll-like receptor 4 signaling is a potent neutrophil activator, but a poor stimulator of survival. In the presence of peripheral blood mononuclear cells (PBMCs), however, pLPS becomes a potent neutrophil survival factor. Interleukin (IL)-1beta has been identified as an important neutrophil activator and prosurvival cytokine, and is produced in abundance by LPS-stimulated PBMCs. We now show that IL-1beta fails to activate highly purified neutrophils or enhance their survival, but in the presence of PBMCs, IL-1beta induces neutrophil survival. We hypothesized that LPS-primed neutrophils might become responsive to IL-1beta, but were unable to demonstrate this. Moreover, IL-1ra failed to prevent pLPS + PBMC-dependent neutrophil survival. In studies of IL-1R1(-/-) mice, we found that LPS was still able to mediate neutrophil survival, and neutrophil survival was enhanced by the addition of monocytic cells. Thus an important paradigm of neutrophil regulation needs to be viewed in the context of a cellular network in which actions of IL-1beta on neutrophils are indirect and mediated by other cells.
authors.affiliation: Academic Unit of Respiratory Medicine, Division of Genomic Medicine, University of Sheffield, M Floor, Royal Hallamshire Hospital, Sheffield S10 2JF, United Kingdom.
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Prince
authors.forename: Lucy
authors.initials: L
authors.lastname: Allen
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Jones
authors.forename: Paul G
authors.initials: PG
authors.lastname: Hellewell
authors.forename: Steven K
authors.initials: SK
authors.lastname: Dower
authors.forename: Moira K B
authors.initials: MK
authors.lastname: Whyte
authors.forename: Ian
authors.initials: I
authors.lastname: Sabroe
mesh_terms: D000818:Animals; D017209:Apoptosis; D039481:CD11b Antigen / Q000096:biosynthesis; D002448:Cell Adhesion; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D019041:L-Selectin / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D019041:L-Selectin