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-chi B 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 LTB4. Involvement of NF-chi B 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-chi B 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-chi B or NF-IL6 in the presence of the scavenger of H2O2, N-acetyl-L-cysteine.

Leukotriene B4 at low dosage negates the catabolic effect of prostaglandin E2 in human patellar tendon fibroblasts

“…The mechanism of LTB 4 -mediated proliferative response is thought to involve protein kinase C (PKC) activation and the stimulation of early response genes such as topoisomerase I and nuclear factor kappa-B (NFκ-B) (Mattern et al, 1990;Brach et al, 1992). In addition, there are interactions between growth stimulatory cytokines such as IL-6, which could potentially mediate LTB 4 -mediated proliferative effects (Brach et al, 1992;RolaPleszczynski and Stankova, 1992;Denzlinger, 1996). The optimal concentration for the leukotriene-induced cytokine production is shown to be in the sub-micromolar range (RolaPleszczynski and Stankova, 1992).…”

fMet-Leu-Phe Stimulates Proinflammatory Cytokine Gene Expression in Human Peripheral Blood Monocytes: The Role of Phosphatidylinositol 3-Kinase

“…The lipid-derived chemoattractants platelet-activating factor (PAF) 3 and leukotriene B4 were shown to activate NF-B in both monocytes (9,11,12) and transfected cell lines expressing the PAF receptor (8). Furthermore, this activation of NF-B in monocytes resulted in the transcription of genes encoding both cytokines and growth factors (9,12).…”

Signaling by the Cysteinyl-Leukotriene Receptor 2

“…NF-B has also been reported to be activated by G-protein-coupled receptor signaling (43,44). Our data show that a mutation in the NF-B site within the IL-8 reporter construct reduced the IL-8 promoter activity induced by LTC 4 in 293LT2 cells by 90%, indicating a major role for the NF-B transcription factor in CysLT2 signaling.…”