NF-κB as a target for anti-inflammatory gene therapy: suppression of inflammatory responses in monocytic and stromal cells by stable gene transfer of IκBα cDNA

Makarov, S.S.; Johnston, WN; Olsen, JC; Watson, JM; Mondal, Krishna; Rinehart, Clifford A.; Haskill, J. S.

doi:10.1038/sj.gt.3300461

Cited by 57 publications

(40 citation statements)

References 4 publications

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“…It is believed that LPS may stimulate the expression of proinflammatory cytokines through a common signaling pathway during inflammation. There is reasonably good evidence that production of TNF-␣, IL-1␤, and IL-6 can be regulated by the transcription factor NF-B in various cell types (33)(34)(35)(36)(37). However, little is known concerning the regulation of hIL-10.…”

Section: Discussionmentioning

confidence: 99%

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The p38 Mitogen-activated Kinase Pathway Regulates the Human Interleukin-10 Promoter via the Activation of Sp1 Transcription Factor in Lipopolysaccharide-stimulated Human Macrophages

Ma¹,

Lim²,

Gee³

et al. 2001

Journal of Biological Chemistry

291

293

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Interleukin-10 (IL-10), a pleiotropic cytokine that inhibits inflammatory and cell-mediated immune responses, is produced by a wide variety of cell types including T and B cells and monocytes/macrophages. Regulation of pro-and anti-inflammatory cytokines has been suggested to involve distinct signaling pathways. In this study, we investigated the regulation of the human IL-10 (hIL-10) promoter in the human monocytic cell line THP-1 following activation with lipopolysaccharide (LPS). Analysis of hIL-10 promoter sequences revealed that DNA sequences located between base pairs ؊652 and ؊571 are necessary for IL-10 transcription. A computer analysis of the promoter sequence between base pairs ؊652 and ؊571 revealed the existence of consensus sequences for Sp1, PEA1, YY1, and EpsteinBarr virus-specific nuclear antigen-2 (EBNA-2)-like transcription factors. THP-1 cells transfected with a plasmid containing mutant Sp1 abrogated the promoter activity, whereas plasmids containing the sequences for PEA1, YY1, and EBNA-2-like transcription factors did not influence hIL-10 promoter activity. To understand the events upstream of Sp1 activation, we investigated the role of p38 and extracellular signal-regulated kinase mitogenactivated protein kinases by using their specific inhibitors. SB202190 and SB203580, the p38-specific inhibitors, inhibited LPS-induced IL-10 production. In contrast, PD98059, a specific inhibitor of extracellular signal-regulated kinase kinases, failed to modulate IL-10 production. Furthermore, SB203580 inhibited LPS-induced activation of Sp1, as well as the promoter activity in cells transfected with a plasmid containing the Sp1 consensus sequence. These results suggest that p38 mitogen-activated protein kinase regulates LPS-induced activation of Sp1, which in turn regulates transcription of the hIL-10 gene.

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Section: Discussionmentioning

confidence: 99%

“…Transcription factors including Rel, C/RBP, AP-1, and NF-B have been implicated in the regulation of proinflammatory cytokine genes (32)(33)(34)(35)(36)(37). However, very little is known about the regulation of the hIL-10 gene and the involvement of MAP kinases in this process.…”

mentioning

confidence: 99%

The p38 Mitogen-activated Kinase Pathway Regulates the Human Interleukin-10 Promoter via the Activation of Sp1 Transcription Factor in Lipopolysaccharide-stimulated Human Macrophages

Ma¹,

Lim²,

Gee³

et al. 2001

Journal of Biological Chemistry

291

293

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show abstract

“…Thus, I B␣ overexpression, or transfection with NF B decoy consensus binding sites decreased NF B activity in endothelial and stromal cells and monocytes in vitro. [19][20][21] This has been extended to animal models of inflammation such as ischemiareperfusion injury and septic shock. 22,23 …”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory gene therapy directed at the airway epithelium

Griesenbach¹,

Scheid²,

Hillery³

et al. 2000

Gene Ther

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“…Blocking signal transduction Makarov 42 was the first to draw attention to the central role of NF-kB in the expression of genes associated with inflammation and tissue destruction in arthritis. Genebased approaches to blocking this transcription factor include using adenovirus to deliver 'super' IkB (inhibitor of NF-kB that is resistant to phosphorylation and thus proteosomal degradation), 43 or a dominant negative form of IKK-b (IkB kinase-b), 44 as well as transfection with decoy oligonucleotides.…”

Section: 41mentioning

confidence: 99%