Role of type I interferons during macrophage activation by lipopolysaccharide.
Activation of macrophages by bacterial lipopolysaccharide (LPS) is accompanied by the secretion of type I interferons (IFNs) which can act in an autocrine manner. We examined the role of type I IFNs in macrophage responses to LPS using bone marrow-derived macrophages (BMM) from IFNAR1-/- mice, which lack a component of the type I IFN receptor and do not respond to type I IFNs. We found that, unlike wild-type (WT) BMM, LPS-treated IFNAR1-/- cells failed to produce nitric oxide (NO), or express inducible NO synthase (iNOS), indicating that type I IFNs are essential for all LPS-stimulated NO production in BMM. Exogenously added type II IFN (IFNgamma) rescued these responses in LPS-treated IFNAR1-/- BMM. In contrast to effects on NO, type I IFNs negatively regulated respiratory burst activity in LPS-primed BMM. We also found that while type I IFNs mediated the anti-proliferative effects of lower concentrations of LPS, at higher concentrations LPS acted in a type I IFNs-independent manner. Finally, we report that type I IFNs are a survival factor for BMM. Despite this, the ability of LPS to also prevent apoptosis in BMM was independent of type I IFNs. These findings highlight the diverse roles of type I IFNs in mediating LPS-stimulated macrophage responses.
Vadiveloo
P K
PK
The Bernard O'Brien Institute of Microsurgery, Fitzroy, 3065, Australia. vadivep@svhm.org.au
Vairo
G
G
Hertzog
P
P
Kola
I
I
Hamilton
J A
JA
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008262:Macrophage Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010101:Oxygen Consumption; D011994:Recombinant Proteins / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D007370:Interferon Type I; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D013481:Superoxides; D009569:Nitric Oxide; D004247:DNA; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse