Leukotriene B4 transcriptionally activates interleukin‐6 expression involving NK‐xB and NF‐IL6

Abstract

Leukotriene B₄ (LTB₄) is a notable participant in inflammation and chemotaxis. It is, however, still unclear whether LTB₄ acts in this regard directly or indirectly by stimulating the release of chemotactic and inflammatory cytokines. Here we report that LTB₄ induces synthesis of interleukin (IL)-6 by human blood monocytes through transcriptional activation of the IL-6 gene. We furthermore demonstrate that this process involves activation of the transcription factor NF-xB and, to a lesser extent, of NF-IL6, while the activity of the transcription factor AP-1, shown to otherwise confer IL-6 inducibility, appeared to be unaffected by LTB_4. Involvement of NF-xB and NF-IL6 in induction of IL-6 transcription by monocytes was demonstrated using deleted forms of the IL-6 promoter. Activation of the IL-6 promoter by LTB₄ was not only associated with accumulation of the respective transcripts but resulted in synthesis of functional IL-6 protein as well. In addition, LTB₄ mediated transactivation of a heterologous promoter construct containing the NF-xB or the NF-IL6 enhancer, but not the AP-1 enhancer. The signaling events mediating this effect appeared to involve the release of H₂O₂, since LTB₄ failed to induce NF-xB or NF-IL6 in the presence of the scavenger of H₂O₂, N-acetyl-L-cysteine.