Interleukin-12 increases interleukin 8 production and release by human polymorphonuclear neutrophils.
Interleukin (IL) 12 is a heterodimeric cytokine mainly produced by phagocytes-important target cells for IL-12 in particular with a chemotactic effect-and antigen-presenting cells in response to various microorganisms. Because IL-8 is a strong chemokine for polymorphonuclear neutrophils (PMNs), we investigated the effect of IL-12 on PMN IL-8 production. IL-12 alone had no significant effect, but with lipopolysaccharide (LPS) it was additive at both protein and mRNA levels. Actinomycin D at the beginning of culture inhibited IL-8 mRNA induction, whereas late addition affected IL-8 transcript stability, suggesting gene transcription involvement. Results with parthenolide and tyrphostin AG490 suggest that nuclear factor-kappaB and signal transducer and activator of transcription 4 play a role. The IL-12 additive effect was restricted to IL-8 release, with no action on cell-associated IL-8. IL-12 additive effects occurred after 18 h of culture, with no marked up-regulation of IL-12 receptor expression, and were blocked by actinomycin D added after 16 h of culture. Tumor necrosis factor (TNF) alpha and interferon (IFN) gamma had intermediate roles; their specific inhibition reduced IL-12's effect. IL-12's chemotactic mechanism seemed mediated by overproduction and release of IL-8 by human PMNs in the presence of LPS, an effect involving TNF-alpha and IFN-gamma secretion. These results point to a new role for IL-12 in inflammation, through an autocrine amplification loop.
Ethuin
F
F
Laboratoire d'Immunologie and Unité INSERM 479, Hôpital Bichat, Paris, France.
Delarche
C
C
Benslama
S
S
Gougerot-Pocidalo
M A
MA
Jacob
L
L
Chollet-Martin
S
S
D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D016753:Interleukin-10 / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D015534:Trans-Activators / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D016207:Cytokines; D004268:DNA-Binding Proteins; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D003907:Dexamethasone; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor