Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis.
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-1beta 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-alpha 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.
Jia
Song Hui
SH
Department of Surgery, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada.
Li
Yue
Y
Parodo
Jean
J
Kapus
Andras
A
Fan
Lingzhi
L
Rotstein
Ori D
OD
Marshall
John C
JC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D016466:CHO Cells; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003470:Culture Media / Q000032:analysis; D016207:Cytokines / Q000378:metabolism*; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D016209:Interleukin-8 / Q000494:pharmacology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D054409:Nicotinamide Phosphoribosyltransferase; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D018805:Sepsis / Q000097:blood* / Q000473:pathology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D003470:Culture Media; D016207:Cytokines; D007375:Interleukin-1; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016376:Oligonucleotides, Antisense; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D020169:Caspases