Distinct mechanisms for regulation of the interleukin-8 gene involve synergism and cooperativity between C/EBP and NF-kappa B.

Stein, B; Baldwin, Albert S.

doi:10.1128/mcb.13.11.7191

Cited by 355 publications

(284 citation statements)

References 29 publications

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“…These observations suggest the presence of p65 homodimers and p65/p50 heterodimers following IL-1␤-stimulation, consistent with earlier observations (26). Although controversy exists in the literature (21,23), employing RA FLS, only NF-B p65 bound to the IL-8 B oligonucleotide, and no NF-B p50 containing heterodimers or p50 homodimers were observed. In a previous study, using RA FLS, antisense oligonucleotides to NF-B p65, and c-Rel, but not NF-B p50, partially inhibited the IL-1␤-stimulated IL-8 secretion by RA FLS, suggesting a potential role for c-Rel (53).…”

Section: Discussionsupporting

confidence: 80%

“…Binding sites for each of these transcription factors have been identified in the promoter regions of the IL-6 and IL-8 genes, and under certain conditions each factor has been shown to activate both proinflammatory genes (17)(18)(19)(20)(21)(22)(23)(24)(25). Furthermore, each of these transcription factors has been implicated in IL-6 and IL-8 expression in RA synovial tissue (26 -29).…”

mentioning

confidence: 99%

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Regulation of IL-6 and IL-8 Expression in Rheumatoid Arthritis Synovial Fibroblasts: the Dominant Role for NF-κB But Not C/EBPβ or c-Jun

Georganas

Liu

Perlman

et al. 2000

The Journal of Immunology

203

134

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Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) produce IL-6 and IL-8, which contribute to inflammation and joint damage. The promoters of both cytokines possess binding sites for NF-κB, C/EBPβ, and c-Jun, but the contribution of each to the regulation of IL-6 and IL-8 in RA FLS is unknown. We employed adenoviral-mediated gene delivery of a nondegradable IκBα, or dominant-negative versions of C/EBPβ or c-Jun, to determine the contribution of each transcription factor to IL-6 and IL-8 expression. Inhibition of NF-κB activation significantly reduced the spontaneous and IL-1β-induced secretion of IL-6 and IL-8 by RA FLS and the IL-1β-induced production of IL-6 and IL-8 by human dermal fibroblasts. Inhibition of C/EBPβ modestly reduced constitutive and IL-1β-induced IL-6 by RA FLS, but not by human dermal fibroblasts, and had no effect on IL-8. Inhibition of c-Jun/AP-1 had no effect on the production of either IL-6 or IL-8. Employing gel shift assays, NF-κB, C/EBPβ, and c-Jun were constitutively activated in RA FLS, but only NF-κB and c-Jun activity increased after IL-1β. The reduction of cytokines by IκBα was mediated through inhibition of NF-κB activation, which resulted in decreased IL-6 and IL-8 mRNA. NF-κB was essential for IL-6 expression, because fibroblasts in which both NF-κB p50/p65 genes were deleted failed to express IL-6 in response to IL-1. These findings document the importance of NF-κB for the regulation of the constitutive and IL-1β-stimulated expression of IL-6 and IL-8 by RA FLS and support the role of inhibition of NF-κB as a therapeutic goal in RA.

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

Regulation of IL-6 and IL-8 Expression in Rheumatoid Arthritis Synovial Fibroblasts: the Dominant Role for NF-κB But Not C/EBPβ or c-Jun

Georganas

Liu

Perlman

et al. 2000

The Journal of Immunology

203

134

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“…The assemblage of transcriptional factor consensus binding elements within the IL-8 promoter is considerably different from those found within promoters of the MCP-1 and RANTES genes (33,40,41). Therefore, we can speculate that these two chemokine genes are unresponsive to stimulation in these experiments either because one or more of the specific transcriptional factors needed to induce MCP-1 and RANTES genes are missing in HCEC or because transcriptional factors needed to up-regulate the two genes are not activated by the same stimuli responsible for IL-8 gene activation.…”

Section: Discussionmentioning

confidence: 99%

“…IL-8 gene expression in CGRP-stimulated cells could potentially be induced at either the level of IL-8-specific RNA synthesis or at the level of IL-8 mRNA stability (31)(32)(33)(34). To determine whether increases in specific RNA synthesis contribute to the enhanced IL-8 production observed in CGRP-stimulated cells, IL-8 premRNA levels were measured by RT-PCR.…”

Section: Cgrp Stimulates Il-8 Gene Expression By Enhancing Il-8-specimentioning

confidence: 99%

Calcitonin Gene-Related Peptide Induces IL-8 Synthesis in Human Corneal Epithelial Cells

Tran

Ritchie

Lausch

et al. 2000

The Journal of Immunology

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Calcitonin gene-related peptide (CGRP), a neuropeptide with proinflammatory activities, is released from termini of corneal sensory neurons in response to pain stimuli. Because neutrophil infiltration of the clear corneal surface is a hallmark of corneal inflammation in the human eye, we determined whether CGRP can bind to human corneal epithelial cells (HCEC) and induce expression of the neutrophil chemotactic protein IL-8. It was found that HCEC specifically bound CGRP in a saturable manner with a Kd of 2.0 × 10−9 M. Exposure of HCEC to CGRP induced a significant increase in intracellular cAMP levels and enhanced IL-8 synthesis nearly 4-fold. The capacity of CGRP to stimulate cAMP and IL-8 synthesis was abrogated in the presence of the CGRP receptor antagonist CGRP8–37. CGRP stimulation had no effect on the half-life of IL-8 mRNA while increasing IL-8 pre-mRNA synthesis >2-fold. In contrast to IL-8, CGRP did not induce monocyte chemotactic protein-1 or RANTES synthesis, nor did the neuropeptide enhance detectable increases in steady state levels of mRNA specific for these two β-chemokines. The results suggest that HCEC possess CGRP receptors capable of initiating a signal transduction cascade that differentially activates expression of the IL-8 gene but not the genes for monocyte chemotactic protein-1 or RANTES. The capacity of CGRP to stimulate IL-8 synthesis in HCEC suggests that sensory neurons are involved in induction of acute inflammation at the eye surface.

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“…Understanding this delicate balance is essential to appreciate the complexity of macrophage biology. A large number of studies have been devoted to the dissection of the molecular mechanisms involved in the regulation of proinflammatory cytokine gene expression, which unveiled several important transcription factor families that mediate inflammatory response of macrophages such as NF-kB, NF-IL6, C/EBP, and interferon regulatory factors [89][90][91][92][93][94][95][96]. In contrast, much less is known about the regulation of anti-inflammatory cytokines.…”

Section: Il-10 Gene Expression In Microbe-and Cytokine-activated Macrmentioning

confidence: 99%

Regulation of cytokine production during phagocytosis of apoptotic cells

2006

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Loss of self-tolerance and expansion of auto-reactive lymphocytes are the basis for autoimmunity. Apoptosis and the rapid clearance of apoptotic cells by phagocytes usually occur as coordinated processes that ensure regulated cellularity and stress response with non-pathological outcomes. Defects in clearance of apoptotic cells would contribute to the generation of self-reactive lymphocytes, which drive autoimmune disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The IL-12 family of cytokines (IL-12, IL-23, and IL-27) and IL-10 are produced by phagocytic macrophages and play critical roles in the regulation of antigen-presenting cells (APCs) and effector lymphocytes during an immune response to pathogens. Inappropriate expression of these cytokines and their dysregulated activities have been strongly implicated in the pathogenesis of several autoimmune diseases. The production of pro-and anti-inflammatory cytokines by phagocytic APCs is delicately regulated during the ingestion of apoptotic cells as part of an intrinsic mechanism to prevent inflammatory autoimmune reactions. How apoptotic cell-derived signals regulate cytokine production is poorly understood. A recent study by our group demonstrated that phagocytosis of apoptotic cells by activated macrophages results in strong inhibition of IL-12 p35 gene expression by activating a novel transcription repressor, which we named GC-binding protein (GC-BP), through tyrosine dephosphorylation. We are also beginning to understand the molecular mechanisms underlying apoptotic cell-triggered production of IL-10 by phagocytes. These studies will help to elucidate some novel immune regulatory mechanisms and explore the regulation of immune responses to autoantigens with potentials to discover new therapeutic targets for the treatment of autoimmune disorders.

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Distinct mechanisms for regulation of the interleukin-8 gene involve synergism and cooperativity between C/EBP and NF-kappa B.

Cited by 355 publications

References 29 publications

Regulation of IL-6 and IL-8 Expression in Rheumatoid Arthritis Synovial Fibroblasts: the Dominant Role for NF-κB But Not C/EBPβ or c-Jun

Regulation of IL-6 and IL-8 Expression in Rheumatoid Arthritis Synovial Fibroblasts: the Dominant Role for NF-κB But Not C/EBPβ or c-Jun

Calcitonin Gene-Related Peptide Induces IL-8 Synthesis in Human Corneal Epithelial Cells

Regulation of cytokine production during phagocytosis of apoptotic cells

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