Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8.

Matsusaka, Taiji; Fujikawa, Keiko; Nishio, Yukihiro; Mukaida, Naofumi; Matsushima, Koji; Kishimoto, Tadamitsu; Akira, Shizuo

doi:10.1073/pnas.90.21.10193

Cited by 894 publications

(658 citation statements)

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“…It was shown that the protein and mRNA levels of both IL-6 and IL-8 increase almost simultaneously in a dose-dependent manner. The finding that both cytokines were induced simultaneously is in line with the results of a recent study by Matsusaka et al [12] showing that the IL-I-induced gene transcription of both IL-6 and IL-8 is synergistically activated by similar tran scription factors, namely NF-IL-6 and NF-kB.…”

Section: Discussionsupporting

confidence: 90%

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Role of fibroblasts in the regulation of proinflammatory interleukin IL-1, IL-6 and IL-8 levels induced by keratinocyte-derived IL-1

et al. 1996

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In the epidermis, the keratinocytes are the first cells to be encountered by external stimuli and they are able to promote the inflammatory response by increased production and release of various cytokines. In their turn, these cytokines may directly affect the production of proinflammatory cytokines in human dermal fibroblasts. In addition, in both epithelial and mesenchymal cells cytokine production may be modu lated by their mutual interaction, and thereby regulate the inflammatory response. The present study aimed to examine the role of fibroblasts in the regulation of proinflammatory IL-1, IL-6 and IL-8 levels induced by keratinocyte-derived IL-1. The data show that in fibroblasts exposed to conditioned media derived from cultures of normal human keratinocytes or squamous carcinoma cells (SCC-4), both the IL-8 and IL-6 mRNA expression as well as protein production were elevated. In addition, it was shown that these effects subsequent internalization and intracellular degrada tion is the most likely mechanism involved in the re duction of IL-1 levels by fibroblasts. Comparing the rate of IL-1 reduction in the presence of various cell types indicated that the rate of IL-1 reduction is di rectly related to the number of IL-1 receptors found on these cell types. In conclusion, these results indicate that the release of IL -la by activated keratinocytes may act as an inducer of IL-8 and IL-6 production in neighbouring fibroblasts. This may be an important pathway for the amplification of the inflammatory re sponse. The amounts of both cytokines produced by fi broblasts were at least two to three orders of magni tude higher than those produced by keratinocytes, suggesting an important role of fibroblasts in the gen eral inflammatory response. Furthermore, fibroblasts might be involved in turning off this inflammatory re sponse by reducing IL-1 levels, most likely via IL-1 rewere induced by IL -la . The IL -la-induced increase in ceptor-mediated uptake. IL-8 and IL-6 production, both on the protein level as well as on the mRNA level, were concentration depen dent and occurred almost simultaneously. W hile the induction of IL-6 and IL-8 occurred simultaneously, the IL-6 mRNA remained elevated for longer. In con-------------------trast to increased IL-6 and IL-8 production the I L -la IntroductionKey words Interleukin-8 ■ Interleukin-1 ♦ IL-l receptor ratinoeyte -Fibroblast interaction levels markedly decreased upon culturing o f fibro blasts in keratinocyte-derived conditioned medium. rr h e r e is increasing evidence that the release and producFrom internalization experiments it could be con-tion of cytokines, either preformed o.r newly synthesized, eluded that binding of IL-1 to IL-1 receptors, and its by keratinocytes and fibroblasts is altered after certain events, such as skin injury [I], The keratinocytes become 'activated1 and release, amongst other things, the proin flammatory cytokine interleukin-1 (IL-1) |2 |. It has been shown that exposure of skin cells to IL-l leads to an in creased production...

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Section: Discussionsupporting

confidence: 90%

“…It has been shown that the transcription factors NF-IL-6 and NF-kB are needed for IL-1-induced IL -6 and IL-8 gene expression [12]. The present study aimed to examine the kinetics of induction of IL-6 and IL-8 production in human dermal fibroblasts by conditioned medium derived from keratinocyte cul tures and by IL -la .…”

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confidence: 95%

Role of fibroblasts in the regulation of proinflammatory interleukin IL-1, IL-6 and IL-8 levels induced by keratinocyte-derived IL-1

et al. 1996

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“…The IL-6 gene promoter contains binding sites for other transcription factors than NFkB, including AP-1, MRE and NF-IL6 transcription factors. [36][37][38][39] Both AP-1 and NF-IL6 have been shown to be involved in the regulation of IL-1b-induced IL-6 expression. 36,37,40 However, NFkB has been considered to be the predominant transcription factor regulating the IL-6 gene in response to inflammatory stimuli.…”

Section: Discussionmentioning

confidence: 99%

Cellular delivery of a double-stranded oligonucleotide

et al. 2004

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The activation of nuclear factor kB (NFkB) is a key event in immune and inflammatory responses. In this study, a cellpenetrating transport peptide, transportan (TP) or its shorter analogue TP 10, was used to facilitate the cellular uptake of an NFkB decoy. Peptide nucleic acid (PNA) hexamer or nonamer was linked to the transport peptide by a disulfide bond. NFkB decoy oligonucleotide consisted of a doublestranded consensus sequence corresponding to the kB site localized in the IL-6 gene promoter, 5 0 -GGGACTTTCCC-3 0 , with a single-stranded protruding 3 0 -terminal sequence complementary to the PNA sequence was hybridized to the transport peptide-PNA construct. The ability of the transport peptide-PNA-NFkB decoy complex to block the effect of interleukin (IL)-1b-induced NFkB activation and IL-6 gene expression was analyzed by electrophoretic mobility shift assay and reverse transcriptase-polymerase chain reaction in rat Rinm5F insulinoma cells. Preincubation with transport peptide-PNA-NFkB decoy (1 mM, 1 h) blocked IL-1b-induced NFkB-binding activity and significantly reduced the IL-6 mRNA expression. The same concentration of NFkB decoy in the absence of transport peptide-PNA had no effect even after longer incubations. Our results showed that binding of the oligonucleotide NFkB decoy to the nonamer PNA sequence resulted in a stable complex that was efficiently translocated across the plasma membrane.

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“…One consequence of this dysregulated NF-κB activity 23,55-58,61-68 is that there is constitutive transcription of the NF-κB-dependent chemokines CXCL1 and CXCL8 in human tumours [90][91][92][93][94][95][96] . Constitutive expression of these chemokines can transform immortalized melanocytes and is associated with increased metastasis in colon carcinoma, squamous-cell carcinoma and melanoma 19, 28,91,97 .…”

Section: Activation Of Nf-κb Enhances Chemokine Transcriptionmentioning

confidence: 99%

“…Whereas cooperation between NF-κB and either AP1 or the CCAAT/enhancer-binding protein (C/EBP) element is required for the transcriptional modulation of CXCL8 (REF. 96), for CXCL1, NF-κB cooperates with a transcription factor that binds to GC-rich complexes (SP1), the high-mobility group protein HMGIY (as determined by an ELECTROPHORETIC MOBILITY-SHIFT ASSAY and immediate upstream region (IUR) elements to modulate the transcription of this chemokine 42 . SP1 and IUR elements are involved in basal and cytokineinduced transcription of the CXCL1 gene.…”

Section: Transcriptional Regulation Of Cxcl1 and Cxcl8mentioning

confidence: 99%

NF-κB, chemokine gene transcription and tumour growth

2002

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The constitutive expression of angiogenic and tumorigenic chemokines by tumour cells facilitates the growth of tumours. The transcription of these angiogenic and tumorigenic chemokine genes is modulated, in part, by the nuclear factor-κB (NF-κB) family of transcription factors. In some tumours, there is constitutive activation of the kinases that modulate the activity of inhibitor of NF-κB (IκB) kinase (IKK), which leads to the constitutive activation of members of the NF-κB family. This activation of NF-κB is associated with the dysregulation of transcription of genes that encode cytokines, chemokines, adhesion factors and inhibitors of apoptosis. In this review, I discuss the factors that lie upstream of the NF-κB cascade that are activated during tumorigenesis and the role of the putative NF-κB enhanceosome in constitutive chemokine gene transcription during tumorigenesis.Chemokines are small, pro-inflammatory peptides; they are often expressed in response to the induction of expression of nuclear factor-κB (NF-κB) by cytokines or other stimuli. Chemokines regulate the transport, activation and, sometimes, proliferation of several cell types, including myeloid, lymphoid, endothelial and epithelial cells 1,2 . There are four chemokine subfamilies -CXC, C, CX 3 C and CC -based on the positions of conserved cysteine residues near the amino terminus of the proteins 1 (TABLE 1). Melanoma growthstimulatory activity (CXCL1) and interleukin-8 (IL-8, CXCL8) are members of the CXCchemokine family, which also includes interferon-γ (IFN-γ)-inducible gene 10 (CXCL10), IFN-inducible T-cell α-chemoattractant (CXCL11), monocyte induced by IFN-γ (CXCL9), epithelial-derived neutrophil-activating peptide 78 (ENA-78, CXCL5), granulocyte chemotactic protein 2 (CXCL6), neutrophil activating peptide 2 (CXCL7), a mitogen for Bcell progenitors known as stromal-derived factor (CXCL12) and B-cell-activating factor 1/Blymphocyte chemoattractant (BCA1/BLC, CXCL13) 1 . The expression of various members of the chemokine superfamily is induced by several cytokines, such as IL-1 and tumour-necrosis factor (TNF), through an NF-κB-mediated event; by IFN-γ through the Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) pathway; or by activating protein 1 (AP1)-mediated transcription. The transcription of chemokine genes is often inhibited by transforming growth factor-β (TGF-β) and glucocorticoids 1 .As the CXC-chemokines CXCL1 and CXCL8 have been associated with tumour growth, metastasis and angiogenesis, I concentrate on these important chemokines. The biological functions of chemokines are mediated through seven-transmembrane G-protein-coupled receptors. CXCL8 and CXCL6 bind to the chemokine receptors CXCR1 and CXCR2, whereas CXCL1 and other CXC-chemokines that have a Glu-Leu-Arg (ELR) motif at their amino terminus (CXCL2, -3 and-5) bind to and activate CXCR2 only 2 . There are also viral receptors Both the CXC-chemokines and their receptors, and the CC-chemokines and their receptors, are involved in ...

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Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8.

Cited by 894 publications

References 30 publications

Role of fibroblasts in the regulation of proinflammatory interleukin IL-1, IL-6 and IL-8 levels induced by keratinocyte-derived IL-1

Role of fibroblasts in the regulation of proinflammatory interleukin IL-1, IL-6 and IL-8 levels induced by keratinocyte-derived IL-1

Cellular delivery of a double-stranded oligonucleotide

NF-κB, chemokine gene transcription and tumour growth

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