Rac1 Negatively Regulates Lipopolysaccharide-Induced IL-23 p19 Expression in Human Macrophages and Dendritic Cells and NF-κB p65 <i>trans</i> Activation Plays a Novel Role

Utsugi, Mitsuyoshi; Dobashi, Kunio; Ishizuka, Tamotsu; Kawata, Takefumi; Hisada, Takeshi; Shimizu, Yasuo; Ono, Akiko; Mori, Masatomo

doi:10.4049/jimmunol.177.7.4550

Cited by 33 publications

(29 citation statements)

References 38 publications

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“…Therefore, RelA may be necessary for expression of the p19 and p35 subunits but not the p40 subunit. These results are consistent with those of a report showing short interfering RNA against RelA suppresses expression of the p19 subunit but not of p40 (26). However, p19 expression in rela-deficient macrophages was reduced to a lesser extent than in c-rel-deficient macrophages; its level was half that in wild-type cells.…”

Section: Discussionsupporting

confidence: 83%

A Proximal κB Site in the IL-23 p19 Promoter Is Responsible for RelA- and c-Rel-Dependent Transcription

Mise-Omata

Kuroda

Niikura

et al. 2007

The Journal of Immunology

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IL-23 is a heterodimeric cytokine composed of a unique p19 subunit and a common p40 subunit is shared with IL-12. IL-23 promotes the inflammatory response by inducing the expansion of CD4+ cells producing IL-17. The regulation of p19 gene expression has been less studied than that of p40 subunit expression, which in macrophages is well known to be dependent on NF-κB. To clarify the role of NF-κB in expression of the p19 gene, we analyzed mRNA levels in NF-κB-deficient macrophages. As reported to occur in dendritic cells, p19 expression was dramatically reduced in c-rel-deficient macrophages. Moreover, we found that p19 expression was halved in rela-deficient macrophages, but it was enhanced in p52-deficient macrophages. The p19 promoter contains three putative κB sites, located at nt −642 to −632 (κB–642), nt −513 to −503 (κB–513), and nt −105 to −96 (κB–105), between the transcription start site and −937 bp upstream in the p19 promoter region. Although EMSA analysis indicated that both κB–105 and κB–642, but not κB–513, bound to NF-κB in vitro, luciferase-based reporter assays showed that the most proximal κB site, κB–105, was uniquely indispensable to the induction of p19 transcription. Chromatin immunoprecipitation demonstrated in vivo association of RelA, c-Rel, and p50 with κB–105 of the p19 promoter. These results provide the evidence that the association of RelA and c-Rel with the proximal κB site in the p19 promoter is required to induce of p19 expression.

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Section: Discussionsupporting

confidence: 83%

A Proximal κB Site in the IL-23 p19 Promoter Is Responsible for RelA- and c-Rel-Dependent Transcription

Mise-Omata

Kuroda

Niikura

et al. 2007

The Journal of Immunology

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“…MD-macrophages and MD-DCs were generated as previously described (15,16). PBMCs were separated by density gradient centrifugation from leukocyte concentrates obtained from healthy adult donors who signed informed consent to allow the use of their blood for research purposes, and monocytes were purified from PBMCs by positive selection with anti-CD14 magnetic beads (Miltenyi Biotec).…”

Section: Cell Culturementioning

confidence: 99%

PI3K p110β Positively Regulates Lipopolysaccharide-Induced IL-12 Production in Human Macrophages and Dendritic Cells and JNK1 Plays a Novel Role

Utsugi

Dobashi

Ono

et al. 2009

The Journal of Immunology

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The PI3K family is thought to participate in TLR signaling, and it has been reported to be a negative regulator of TLR-mediated production of IL-12, a key inducer of Th1 responses. However, the role of individual PI3K subtypes in IL-12 production remains obscure. We defined the distinct regulation of LPS-mediated IL-12 production by p110α and p110β catalytic subunits of PI3K in human APCs. We observed that knockdown of PI3K p110β by small interfering RNA (siRNA) suppressed both LPS-induced IL-12 protein production and mRNA expression in monocyte-derived macrophages and dendritic cells (DCs). Knockdown of PI3K p110α by siRNA reduced LPS-induced IL-12 protein production in both cell types. Conversely, knockdown of PI3K p110α suppressed LPS-induced IL-12 mRNA expression in monocyte-derived macrophages but minimally affected monocyte-derived DCs. PI3K p110β siRNA inhibited JNK activation, but not p38 MAPK or ERK activation, stimulated by LPS, while PI3K p110α siRNA did not affect LPS-induced JNK, p38 MAPK, or ERK activation in both cell types. Transfection of siRNA against JNK1, JNK2, and both decreased LPS-induced IL-12 production. Furthermore, PI3K p110β siRNA attenuated LPS-induced JNK1 phosphorylation, while not affecting JNK2 phosphorylation. Our findings indicate that PI3K p110β positively controls LPS-induced IL-12 production through the JNK1-dependent pathway in human macrophages and DCs.

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“…Among several roles assigned to RAC1 in inflammation, its participation in cytoskeleton remodeling and chemotaxis as well as in NADPH oxidase-dependent production of superoxide have been well established (4,5). Moreover, RAC1 leads to activation of the transcription factor NF-B and its target genes, including several proinflammatory cytokines such as TNF (4,6). However, it is not known how cells activated by RAC1 ultimately change their gene expression back to a "resting" state or toward a resolution profile.…”

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confidence: 99%

Transcription Factors NRF2 and NF-κB Are Coordinated Effectors of the Rho Family, GTP-binding Protein RAC1 during Inflammation

Cuadrado

Martín‐Moldes

et al. 2014

Journal of Biological Chemistry

280

186

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Background: RAC1 is a small G-protein of the Rho family that activates the transcription factor NF-B to elicit an inflammatory response. Results: We have found that RAC1 also induces the NRF2/ARE pathway, which in term blocks RAC1-dependent NF-B activation. Conclusion: RAC1 modulates inflammation by coordinating the activity of pro-inflammatory NF-B and anti-oxidant NRF2 transcription factors. Significance: Therapeutic intervention on RAC1 could help modulate pro-and anti-inflammatory processes.

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Rac1 Negatively Regulates Lipopolysaccharide-Induced IL-23 p19 Expression in Human Macrophages and Dendritic Cells and NF-κB p65 trans Activation Plays a Novel Role

Cited by 33 publications

References 38 publications

A Proximal κB Site in the IL-23 p19 Promoter Is Responsible for RelA- and c-Rel-Dependent Transcription

A Proximal κB Site in the IL-23 p19 Promoter Is Responsible for RelA- and c-Rel-Dependent Transcription

PI3K p110β Positively Regulates Lipopolysaccharide-Induced IL-12 Production in Human Macrophages and Dendritic Cells and JNK1 Plays a Novel Role

Transcription Factors NRF2 and NF-κB Are Coordinated Effectors of the Rho Family, GTP-binding Protein RAC1 during Inflammation

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