Reactive Oxygen Intermediate-Dependent NF-κB Activation by Interleukin-1β Requires 5-Lipoxygenase or NADPH Oxidase Activity

Abstract

The interaction of interleukin-1␤ (IL-1␤) with its type 1 cell surface receptor initiates a cascade of intracellular reactions leading to the activation of transcription factors and the expression of target genes. One of the major transcription factors mediating IL-1␤ biological activities is NF-B (for reviews, see references 2, 3, and 22). This factor is sequestered in the cytoplasm by an inhibitor from the IB family. IL-1␤ cellular stimulation leads to a rapid phosphorylation and degradation of IB␣, the most common NF-B inhibitor. This reaction allows NF-B to translocate to the nucleus, to bind DNA, and to activate the transcription of specific genes (2, 55).Following its interaction with IL-1, the type 1 IL-1 receptor recruits the IL-1 receptor-associated kinase (IRAK) protein, which subsequently interacts with the TRAF6 adapter protein (15,16,30,61,62,65). TRAF6 is required for IL-1␤-induced NF-B activation, as demonstrated in 293 cells (16).However, the signaling pathways leading to NF-B activation from the IL-1␤ receptors are still controversial. It has been demonstrated that TRAF6 interacts with a MAP kinase kinase kinase (MAPKKK) known as NIK and that NIK is required for IL-1␤-or tumor necrosis factor alpha (TNF-␣)-dependent 56). Large (500 to 900 kDa) multimeric protein kinase complexes have been purified from HeLa cells and transmit the signal from the TNF receptor type 1 (TNFR-1) and type 1 IL-1 receptors to the NF-B/IB cytoplasmic complex (17,20,33,41). From these complexes three IB kinases, IKK-␣, IKK-␤, and IKK-␥, have been purified, and their genes were cloned (20,42,49,66). Other investigators have cloned IKK kinases by virtue of their association with the NIK protein kinase (47, 64). Moreover, inactivation of these kinases by dominant negative mutants suppresses IL-1␤ and TNF-␣ induction of NF-B. These studies indicate that the activated NIK kinase phosphorylates and activates the IKK protein kinases. IKK protein kinases can in turn phosphorylate the IB␣ protein on serines located at positions 32 and 36, a reaction which targets IB␣ for ubiquitination and rapid degradation by the proteasome (12,58,59). These reactions are extremely rapid, and the cellular IB␣ protein is completely degraded within minutes following TNF-␣ or IL-1␤ cell stimulation (4, 13).Despite this simplified linear receptor-TRAF-NIK-IKK axis for IB␣ phosphorylation and degradation, other intermediates might be involved in NF-B activation by TNF-␣ or IL-1␤. First, several components of the large signaling complex remain to be identified, as the three IKK protein kinases do not account for the molecular weight of the whole complex. Second, a large number of studies, some of them being a matter of controversy, have identified other intermediates which seem to be required for TNF-␣-or IL-1␤-mediated NF-B activation. These intermediates are Raf-1, MAP kinases, the PKC and / isoforms, Rho and Rac proteins, and ceramide or reactive oxygen intermediates (ROIs) (19,24,25,32,33,38,46,(50)(51)(52)(53)57). Such a large number of controver...

Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain

“…The stimulatory effects of COX-2 inhibition on IL6 expression are attributed to the inhibitory action of COX-2-derived-PGE 2 on IL6 synthesis (Hartel et al, 2004). Thus, the interesting possibilities for the over-expression of IL6 in the present study might result from (1) removal of the inhibition from COX-2-derived-PGE 2 by rofecoxib-induced reduction of PGE 2 ; (2) deviation of AA production after COX-2 blockage because both accumulation of AA and its oxidation by lipoxygenases can result in up-regulation of pro-inflammatory gene production through the NF-κB dependent pathway (Bonizzi et al, 1999). Additionally, IL6 also induces the expression of anti-inflammatory factor, IL1 receptor antagonist (Tilg, et al, 1994).…”

“…As a consequence of shunting down the cyclooxygenase pathway, the accumulation of AA and the products from lipoxygenase can induce up-regulation of pro-inflammatory cytokines at transcriptional and post-transcriptional levels through the NF-kB pathway (Bonizzi et al, 1999). The changes in gene expression related to lipoxygenase family members (ALOXE3, ALOX12B and ALOX15B) in this study may reflect compensatory reactions from the interruption of the cyclooxygenase pathway by inhibition of COX-2, which may be possibly affecting other inflammatory mediators as discussed below.…”

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

“…In general, the 5-LOX pathway leads to proliferative and pro-apoptotic effects in various forms of cancer, with exogenous 5-HETE and cysteinyl leukotrienes having up to a fourfold proliferative effect on four different types of breast cancer cell lines [79]. Stimulation of 5-LOX activity was found to arise due to tumour necrosis factor α (TNF-α), interleukin 1β (IL-1β) and histamine signalling, ultimately resulting in ROS-mediated NF-κB activation [80,81]. Furthermore, cancer cell growth was demonstrated in human testicular cancer tissue, where both 5-and 12-LOX were found to promote induction of cell proliferation, an effect which was suppressed upon inhibition of 5-LOX [82].…”

Involvement of lipoxygenase in lysophosphatidic acid-stimulated hydrogen peroxide release in human HaCaT keratinocytes

“…Increased amounts of H # O # have also been detected in HeLa cells treated with lysophosphatidic acid (LPA) [6]. In lymphoid cells, interleukin-1β and interleukin-2 produce ROS that mediate NF-κB activation [7,8].…”