scholarly journals Transcriptional regulation of the human TRIF (TIR domain-containing adaptor protein inducing interferon beta) gene

2004 ◽  
Vol 380 (1) ◽  
pp. 83-93 ◽  
Author(s):  
Matthew P. HARDY ◽  
Anne F. McGETTRICK ◽  
Luke A. J. O'NEILL
Keyword(s):  
Interleukin 1 ◽  
Adaptor Protein ◽  
Inducible Promoter ◽  
Nuclear Factor Κb ◽  
Distal Region ◽  
Proximal Region ◽  
Type I ◽  
Gene Encoding ◽  
Interleukin 1Α ◽  
Factor Α

TRIF [TIR (Toll/interleukin-1 receptor) domain-containing adaptor protein inducing interferon β; also known as TICAM-1 (TIR-containing adaptor molecule-1)] is a key adaptor for TLR3 (Toll-like receptor 3)- and TLR4-mediated signalling. We have performed a detailed annotation of the human TRIF gene and fine analysis of the basal and inducible promoter elements lying 5´ to the site of initiation of transcription. Human TRIF maps to chromosome 19p13.3 and is flanked upstream by TIP47, which encodes the mannose 6-phosphate receptor binding protein, and downstream by a gene encoding FEM1a, a human homologue of the Caenorhabditis elegans Feminisation-1 gene. Using promoter–reporter deletion constructs, we identified a distal region with the ability to negatively regulate basal transcription and a proximal region containing an Sp1 (stimulating protein 1) site that confers approx. 75% of basal transcriptional activity. TRIF expression can be induced by multiple stimuli, such as the ligands for TLR2, TLR3 and TLR4, and by the pro-inflammatory cytokines tumour necrosis factor α and interleukin-1α. All of these stimuli act via an NF-κB (nuclear factor-κB) motif at position −127. In spite of the presence of a STAT1 (signal transduction and activators of transcription 1) motif at position −330, the addition of type I or type II interferon had no effect on TRIF activity. The human TRIF gene would therefore appear to be regulated primarily by NF-κB.

scholarly journals Expression of interleukin-1α and interleukin-1 receptor type I genes in murine brown adipose tissue

FEBS Letters ◽  
1993 ◽  
Vol 334 (2) ◽  
pp. 229-232 ◽  
Author(s):  
Ladislav Burýs̆ek ◽  
Petr Tvrdí ◽  
Josef Hous̆tĕk
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Interleukin 1 ◽  
Receptor Type ◽  
Type I ◽  
Brown Adipose ◽  
Interleukin 1Α

scholarly journals Intracellular Interleukin-1α Mediates Interleukin-8 Production Induced by Chlamydia trachomatis Infection via a Mechanism Independent of Type I Interleukin-1 Receptor

2007 ◽  
Vol 76 (3) ◽  
pp. 942-951 ◽  
Author(s):  
Wen Cheng ◽  
Pooja Shivshankar ◽  
Youmin Zhong ◽  
Ding Chen ◽  
Zhongyu Li ◽  
...  
Keyword(s):  
Chlamydia Trachomatis ◽  
Early Stage ◽  
Interleukin 1 ◽  
Type I ◽  
Infection Cycle ◽  
Chlamydia Trachomatis Infection ◽  
Cytokines And Chemokines ◽  
Intracellular Mechanism ◽  
Interleukin 1Α ◽  
Interfering Rna

ABSTRACT Chlamydia trachomatis infection induces a wide array of inflammatory cytokines and chemokines, which may contribute to chlamydia-induced pathologies. However, the precise mechanisms by which Chlamydia induces cytokines remain unclear. Here we demonstrate that the proinflammatory cytokine interleukin-1α (IL-1α) plays an essential role in chlamydial induction of the chemokine IL-8. Cells deficient in IL-1α expression or IL-1α-competent cells treated with IL-1α-specific small interfering RNA failed to produce IL-8 in response to chlamydial infection. However, neutralization of extracellular IL-1α or blockade of or deficiency in type I IL-1 receptor (IL-1RI) signaling did not affect chlamydial induction of IL-8 in cells capable of producing IL-1α. These results suggest that IL-1α can mediate the chlamydial induction of IL-8 via an intracellular mechanism independent of IL-1RI, especially during the early stage of the infection cycle. This conclusion is further supported by the observations that expression of a transgene-encoded full-length IL-1α fusion protein in the nuclei enhanced IL-8 production and that nuclear localization of chlamydia-induced precursor IL-1α correlated with chlamydial induction of IL-8. Thus, we have identified a novel mechanism for chlamydial induction of the chemokine IL-8.

6-Gingerol Ameliorates Sepsis Induced Acute Lung Injury by Regulating Nuclear Factor-κB and Nuclear-Factor Erythroid 2-Related Factor 2/Heme Oxygenase-1 Signaling Pathways

2020 ◽  
Vol 19 (3) ◽  
pp. 255-260
Author(s):  
Fan Yang ◽  
Lu Deng ◽  
MuHu Chen ◽  
Ying Liu ◽  
Jianpeng Zheng
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Heme Oxygenase ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Alveolar Collapse ◽  
Factor Α

Acute lung injury initiated systemic inflammation leads to sepsis. Septic mice show a series of degenerative changes in lungs as demonstrated by pulmonary congestion, alveolar collapse, inflammatory cell infiltration, and increased wet-todry weight in lungs. 6-Gingerol ameliorates histopathological changes and clinical outcome of the sepsis. The increase in the levels of tumor necrosis factor-α, interleukin-1 beta, interleukin-6, and interleukin-18 in septic mice were reduced by administration with 6-Gingerol. Also, 6-Gingerol attenuates sepsis-induced increase of malonaldehyde and decrease of catalase, superoxide, and glutathione. Enhanced phospho-p65, reduced nuclear factor erythropoietin-2-related factor 2, and heme oxygenase 1 in septic mice were reversed by administration with 6-Gingerol. In conclusion, 6-Gingerol demonstrates anti-inflammatory and antioxidant effects against sepsis associated acute lung injury through inactivation of nuclear factor-kappa B and activation of nuclear-factor erythroid 2-related factor 2 pathways.

scholarly journals Counter-regulation in the IKK family

2011 ◽  
Vol 434 (1) ◽  
pp. e1-e2 ◽  
Author(s):  
Luke A. J. O'Neill
Keyword(s):  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Control Mechanisms ◽  
Biochemical Journal ◽  
Regulatory Feedback Loop

The human IKK [IκB (inhibitor of NF-κB) kinase] family has four members; they are the central kinases of innate immunity. Two members, IKKα and IKKβ, the so-called canonical members, phosphoryate IκBα, leading to activation of the transcription factor NF-κB (nuclear factor κB), which controls the expression of many immune and inflammatory genes. The IKK-related proteins TBK-1 (TANK-binding kinase 1) and IKKϵ have a different substrate – IRF3 (interferon regulatory factor 3) – which regulates a different set of genes, the products of which include Type I interferons. Toll-like receptors (TLRs) such as the lipopolysaccharide receptor TLR4 or the poly(I:C) receptor TLR3 activate each of the IKKs, but the pro-inflammatory cytokine IL-1 (interleukin 1), which signals in a broadly similar way to the TLRs, has so far been shown to activate only the canonical IKKs. In this issue of the Biochemical Journal, Clark et al. bring new insights into the regulation of IKKs. They demonstrate that IL-1 is in fact able to activate IKKϵ/TBK-1, which occurs via IKKα/IKKβ. The consequence of this is not IRF3 activation, but a negative feedback effect on IKKα/IKKβ. This provides us with yet another regulatory feedback loop in a system already replete with control mechanisms. It attests yet again to the importance of keeping these innate immune pathways in check, since if they proceed uncontrolled, inflammatory diseases can occur. Importantly, this study utilized new and specific inhibitors of these kinases, suggesting that the interpretation of any effects the compound might have in vivo may be complex, since for example the inhibition of IKKϵ/TBK-1 might actually have a pro-inflammatory effect.

scholarly journals The IKKβ Subunit of IκB Kinase (IKK) is Essential for Nuclear Factor κB Activation and Prevention of Apoptosis

1999 ◽  
Vol 189 (11) ◽  
pp. 1839-1845 ◽  
Author(s):  
Zhi-Wei Li ◽  
Wenming Chu ◽  
Yinling Hu ◽  
Mireille Delhase ◽  
Tom Deerinck ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Regulatory Subunit ◽  
Nuclear Factor ◽  
Catalytic Subunits ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Factor Α ◽  
Necrosis Factor

The IκB kinase (IKK) complex is composed of three subunits, IKKα, IKKβ, and IKKγ (NEMO). While IKKα and IKKβ are highly similar catalytic subunits, both capable of IκB phosphorylation in vitro, IKKγ is a regulatory subunit. Previous biochemical and genetic analyses have indicated that despite their similar structures and in vitro kinase activities, IKKα and IKKβ have distinct functions. Surprisingly, disruption of the Ikkα locus did not abolish activation of IKK by proinflammatory stimuli and resulted in only a small decrease in nuclear factor (NF)-κB activation. Now we describe the pathophysiological consequence of disruption of the Ikkβ locus. IKKβ-deficient mice die at mid-gestation from uncontrolled liver apoptosis, a phenotype that is remarkably similar to that of mice deficient in both the RelA (p65) and NF-κB1 (p50/p105) subunits of NF-κB. Accordingly, IKKβ-deficient cells are defective in activation of IKK and NF-κB in response to either tumor necrosis factor α or interleukin 1. Thus IKKβ, but not IKKα, plays the major role in IKK activation and induction of NF-κB activity. In the absence of IKKβ, IKKα is unresponsive to IKK activators.

scholarly journals HIF-1α is a negative regulator of interferon regulatory factors: Implications for interferon production by hypoxic monocytes

2021 ◽  
Vol 118 (26) ◽  
pp. e2106017118
Author(s):  
Travis Peng ◽  
Shin-Yi Du ◽  
Myoungsun Son ◽  
Betty Diamond
Keyword(s):  
Inflammatory Cytokines ◽  
Cell Function ◽  
Hypoxia Inducible Factor ◽  
Human Monocyte ◽  
Nuclear Factor Κb ◽  
Negative Regulator ◽  
Type I ◽  
Hypoxic Conditions ◽  
Stressed Cells ◽  
Factor Α

Patients with severe COVID-19 infection exhibit a low level of oxygen in affected tissue and blood. To understand the pathophysiology of COVID-19 infection, it is therefore necessary to understand cell function during hypoxia. We investigated aspects of human monocyte activation under hypoxic conditions. HMGB1 is an alarmin released by stressed cells. Under normoxic conditions, HMGB1 activates interferon regulatory factor (IRF)5 and nuclear factor-κB in monocytes, leading to expression of type I interferon (IFN) and inflammatory cytokines including tumor necrosis factor α, and interleukin 1β, respectively. When hypoxic monocytes are activated by HMGB1, they produce proinflammatory cytokines but fail to produce type I IFN. Hypoxia-inducible factor-1α, induced by hypoxia, functions as a direct transcriptional repressor of IRF5 and IRF3. As hypoxia is a stressor that induces secretion of HMGB1 by epithelial cells, hypoxia establishes a microenvironment that favors monocyte production of inflammatory cytokines but not IFN. These findings have implications for the pathogenesis of COVID-19.

scholarly journals PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation

2008 ◽  
Vol 205 (2) ◽  
pp. 315-322 ◽  
Author(s):  
Cristiana Guiducci ◽  
Cristina Ghirelli ◽  
Marie-Annick Marloie-Provost ◽  
Tracy Matray ◽  
Robert L. Coffman ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Cell Types ◽  
Nuclear Factor Κb ◽  
Type I ◽  
Endosomal Trafficking ◽  
Type I Ifn ◽  
Protein Levels ◽  
Proinflammatory Responses ◽  
Novel Target ◽  
Factor Α

Plasmacytoid predendritic cells (pDCs) are the main producers of type I interferon (IFN) in response to Toll-like receptor (TLR) stimulation. Phosphatidylinositol-3 kinase (PI3K) has been shown to be activated by TLR triggering in multiple cell types; however, its role in pDC function is not known. We show that PI3K is activated by TLR stimulation in primary human pDCs and demonstrate, using specific inhibitors, that PI3K is required for type I IFN production by pDCs, both at the transcriptional and protein levels. Importantly, PI3K was not involved in other proinflammatory responses of pDCs, including tumor necrosis factor α and interleukin 6 production and DC differentiation. pDCs preferentially expressed the PI3K δ subunit, which was specifically involved in the control of type I IFN production. Although uptake and endosomal trafficking of TLR ligands were not affected in the presence of PI3K inhibitors, there was a dramatic defect in the nuclear translocation of IFN regulatory factor (IRF) 7, whereas nuclear factor κB activation was preserved. Thus, PI3K selectively controls type I IFN production by regulating IRF-7 nuclear translocation in human pDCs and could serve as a novel target to inhibit pathogenic type I IFN in autoimmune diseases.

scholarly journals Multiple regions within the promoter of the murine Ifnar-2 gene confer basal and inducible expression

2002 ◽  
Vol 365 (2) ◽  
pp. 355-367 ◽  
Author(s):  
Matthew P. HARDY ◽  
Paul J. HERTZOG ◽  
Catherine M. OWCZAREK
Keyword(s):  
Splice Variants ◽  
Regulatory Region ◽  
Distal Region ◽  
Inducible Expression ◽  
Luciferase Reporter ◽  
Type I ◽  
Type I Ifn ◽  
Mrna Isoforms ◽  
Gene Encoding ◽  
Multiple Regions

The (murine) type I interferon (IFN) receptor, muIfnar-2, is expressed ubiquitously, and exists as both transmembrane and soluble forms. In the present study we show that the gene encoding muIfnar-2 spans approx. 33kb on mouse chromosome 16, and consists of nine exons and eight introns. The three mRNA splice variants resulting in one transmembrane (muIfnar-2c) and two soluble (muIfnar-2a/2a′) mRNA isoforms are generated by alternative RNA processing of the muIfnar-2 gene. Treatment of a range of murine cell lines with a combination of type I and II IFN showed that the muIfnar-2a and −2c mRNA isoforms were up-regulated independently of each other in L929 fibroblasts and hepa-1c1c7 hepatoma cells, but not in M1 myeloid leukaemia cells. Analysis of the 5′ flanking region of muIfnar-2 using promoter—luciferase reporter constructs defined three regulatory regions: a region proximal to exon 1, conferring high basal expression, a distal region conferring inducible expression, and a negative regulatory region between the two. These data represent the first promoter analysis of a type I IFN receptor and, taken together with our previous data demonstrating high expression levels and dual biological functions for muIfnar-2a protein, suggests that the regulation of muIfnar-2 isoform expression may be an important way of modulating type I IFN responses.

scholarly journals The Type II Heat-Labile Enterotoxins LT-IIa and LT-IIb and Their Respective B Pentamers Differentially Induce and Regulate Cytokine Production in Human Monocytic Cells

2004 ◽  
Vol 72 (11) ◽  
pp. 6351-6358 ◽  
Author(s):  
George Hajishengallis ◽  
Hesham Nawar ◽  
Richard I. Tapping ◽  
Michael W. Russell ◽  
Terry D. Connell
Keyword(s):  
Cytokine Production ◽  
Nuclear Factor Κb ◽  
Type I ◽  
Type Ii ◽  
Cytokine Induction ◽  
Heat Labile ◽  
Tnf Α ◽  
A Subunit ◽  
Anti Inflammatory ◽  
Factor Α

ABSTRACT The type II heat-labile enterotoxins, LT-IIa and LT-IIb, exhibit potent adjuvant properties. However, little is known about their immunomodulatory activities upon interaction with innate immune cells, unlike the widely studied type I enterotoxins that include cholera toxin (CT). We therefore investigated interactions of LT-IIa and LT-IIb with human monocytic THP-1 cells. We found that LT-II enterotoxins were inactive in stimulating cytokine release, whereas CT induced low levels of interleukin-1β (IL-1β) and IL-8. However, all three enterotoxins potently regulated cytokine induction in cells activated by bacterial lipopolysaccharide or fimbriae. Induction of proinflammatory (tumor necrosis factor α [TNF-α]) or chemotactic (IL-8) cytokines was downregulated, whereas induction of cytokines with anti-inflammatory (IL-10) or mucosal adjuvant properties (IL-1β) was upregulated by the enterotoxins. These effects appeared to depend on their A subunits, because isolated B-pentameric subunits lacked regulatory activity. Enterotoxin-mediated inhibition of proinflammatory cytokine induction in activated cells was partially attributable to synergism for endogenous production of IL-10 and to an IL-10-independent inhibition of nuclear factor κB (NF-κB) activation. In sharp contrast to the holotoxins, the B pentamers (LT-IIaB and, to a greater extent, LT-IIbB) stimulated cytokine production, suggesting a link between the absence of the A subunit and increased proinflammatory properties. In this regard, the ability of LT-IIbB to activate NF-κB and induce TNF-α and IL-8 was antagonized by the LT-IIb holotoxin. These findings support distinct immunomodulatory roles for the LT-II holotoxins and their respective B pentamers. Moreover, the anti-inflammatory properties of the holotoxins may serve to suppress innate immunity and promote the survival of the pathogen.

Sign in / Sign up

Export Citation Format

Share Document