Pre–B cell colony–enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis
Song Hui Jia, … , Ori D. Rotstein, John C. Marshall
Song Hui Jia, … , Ori D. Rotstein, John C. Marshall
Published May 1, 2004
Citation Information: J Clin Invest. 2004;113(9):1318-1327. https://doi.org/10.1172/JCI19930.
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Article Infectious disease

Pre–B cell colony–enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis

Abstract

Pre–B cell colony-enhancing factor (PBEF) is a highly conserved 52-kDa protein, originally identified as a growth factor for early stage B cells. We show here that PBEF is also upregulated in neutrophils by IL-1β and functions as a novel inhibitor of apoptosis in response to a variety of inflammatory stimuli. Induction of PBEF occurs 5–10 hours after LPS exposure. Prevention of PBEF translation with an antisense oligonucleotide completely abrogates the inhibitory effects of LPS, IL-1, GM-CSF, IL-8, and TNF-α on neutrophil apoptosis. Immunoreactive PBEF is detectable in culture supernatants from LPS-stimulated neutrophils, and a recombinant PBEF fusion protein inhibits neutrophil apoptosis. PBEF is also expressed in neutrophils from critically ill patients with sepsis in whom rates of apoptosis are profoundly delayed. Expression occurs at higher levels than those seen in experimental inflammation, and a PBEF antisense oligonucleotide significantly restores the normal kinetics of apoptosis in septic polymorphonuclear neutrophils. Inhibition of apoptosis by PBEF is associated with reduced activity of caspases-8 and -3, but not caspase-9. These data identify PBEF as a novel inflammatory cytokine that plays a requisite role in the delayed neutrophil apoptosis of clinical and experimental sepsis.

Authors

Song Hui Jia, Yue Li, Jean Parodo, Andras Kapus, Lingzhi Fan, Ori D. Rotstein, John C. Marshall

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Prevention of PBEF translation with an antisense oligonucleotide blocks ...
Prevention of PBEF translation with an antisense oligonucleotide blocks inhibition of apoptosis in response to inflammatory stimuli. (A) Neutrophil apoptosis, assessed as the nuclear uptake of propidium iodide, was significantly inhibited by coincubation with LPS (1 ∝g/ml), IL-1β (100 pg/ml), GM-CSF (20 ng/ml), IL-8 (250 ng/ml), or TNF-α (40 ng/ml). *P < 0.05 compared with control rates. Prevention of PBEF translation using an antisense oligonucleotide prevented this inhibitory effect; the corresponding sense or scrambled nonsense controls were without effect. Data are mean ± SD of six separate studies. (B) Antisense treatment of resting or LPS-stimulated (1 ∝g/ml) neutrophils inhibited the translation of PBEF as detected by Western blot analysis. Blot is representative of three separate studies. (C) Both LPS (1 ∝g/ml) and recombinant PBEF (50 ng/ml) inhibited phosphatidylserine exteriorization detected by the binding of FITC-labeled annexin V, an effect that was specifically blocked when neutrophils were pretreated with PBEF antisense; n = 4, *P < 0.05. rPBEF, recombinant PBEF.