Interleukin-12: An Update on its Immunological Activities, Signaling and Regulation of Gene Expression

Liu, Jianguo; Cao, Sheng; Kim, Sun Jung; Chung, Elaine Y.; Homma, Yoichiro; Guan, Xiuqin; Jimenez, Violeta; Ma, Xiaojing

doi:10.2174/1573395054065115

Cited by 125 publications

(98 citation statements)

References 221 publications

(238 reference statements)

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“…Higher SOCS3 expression or the IL-10/ID3 signaling loop may interfere with IL-12 expression. Indeed, Wnt5a-DCs failed to properly increase IRF1 and IRF8 transcription after stimulation, two positive and essential factors for priming IL-12 secretion (28).…”

Section: Discussionmentioning

confidence: 99%

Wnt5a Skews Dendritic Cell Differentiation to an Unconventional Phenotype with Tolerogenic Features

Valencia

Hernández-López

Martínez

et al. 2011

The Journal of Immunology

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Dendritic cells (DCs) are critical regulators of immune responses that integrate signals from the innate and adaptive immune system and orchestrate T cell responses toward either immunity or tolerance. Growing evidence points to the Wnt signaling pathway as a pivotal piece in the immune balance and focuses on DCs as a direct target for their immunoregulatory role. Our results show that the increase in Wnt5a signaling during the differentiation of human DCs from monocytes alters their phenotype and compromises their subsequent capacity to mature in response to TLR-dependent stimuli. These Wnt5a-DCs produce scant amounts of IL-12p70 and TNF-α but increased levels of IL-10. Consequently, these Wnt5a-DCs have a reduced capacity to induce Th1 responses that promote IL-10 secretion by CD4 T cells. Changes in the transcriptional profile of Wnt5a-DCs correlate with their unconventional phenotype caused presumably by increased IL-6/IL-10 signaling during the process of DC differentiation. The effect of Wnt5a is not a consequence of β-catenin accumulation but is dependent on noncanonical Ca2+/calmodulin-dependent protein kinase II/NF-κB signaling. Our results therefore suggest that under high levels of Wnt5a, typical of the inflammatory state and sepsis, monocytes could differentiate into unconventional DCs with tolerogenic features.

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Section: Discussionmentioning

confidence: 99%

Wnt5a Skews Dendritic Cell Differentiation to an Unconventional Phenotype with Tolerogenic Features

Valencia

Hernández-López

Martínez

et al. 2011

The Journal of Immunology

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“…This suggests that the difference between our study and that of Lucas et al (68) may be attributable to cross-talk between ERK1/2-mediated signaling and the PI3K-AKT pathway because only the latter was inhibited in our study. The regulation of IL-12 mRNA expression has been described extensively in a recent review (69) and is dependent upon the coordinated expression of IL-12 IL-12b and IL-12a genes, which are encoded on different chromosomes. Many studies have confirmed that the primary regulatory step for the expression of both IL-12 IL-12b and IL-12a genes is at the level of transcription: multiple transcription factors are known to be involved in regulation of these genes, e.g., NF-B (47), C/EBP␤ (41), PU.1 (70), IRF-1 (37, 71), IRF-2 (37), IRF-8/ICSBP (50,51), NFAT (72), AP-1 (73), and activator and repressor factors such as Kruppellike factor (74).…”

Section: Discussionmentioning

confidence: 99%

Role of Phosphatidylinositol-3 Kinase in Transcriptional Regulation of TLR-Induced IL-12 and IL-10 by Fcγ Receptor Ligation in Murine Macrophages

Polumuri

Toshchakov

Vogel

2007

The Journal of Immunology

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Ligation of FcγR concurrent with LPS stimulation of murine macrophages results in decreased IL-12 and increased IL-10 production. Because PI3K deficiency has been associated with increased IL-12, we hypothesized that PI3K was central to the anti-inflammatory effect of FcγR ligation on TLR-induced IL-12. FcγR ligation of macrophages increased pAKT, a correlate of PI3K activity, above levels induced by TLR4 or TLR2 agonists. This increase was blocked by PI3K inhibitors, wortmannin or LY294002, as was the effect of FcγR ligation on TLR-induced IL-12 and IL-10. LPS-induced binding of NF-κB to the IL-12 p40 promoter NF-κB-binding site was not affected by FcγR ligation at 1 h; however, by 4 h, NF-κB binding was markedly inhibited, confirmed in situ by chromatin immunoprecipitation analysis. This effect was wortmannin sensitive. Although TLR-induced IκBα degradation was not affected by FcγR ligation, IκBα accumulated in the nuclei of cells treated with LPS and FcγR ligation for 4 h, and was blocked by PI3K inhibitors. LPS-induced IFN regulatory factor-8/IFN consensus sequence-binding protein mRNA, and an IFN regulatory factor-8-dependent gene, Nos2, were inhibited by concurrent FcγR ligation, and this was also reversed by wortmannin. Thus, FcγR ligation modulates LPS-induced IL-12 via multiple PI3K-sensitive pathways that affect production, accumulation, and binding of key DNA-binding proteins required for IL-12 induction.

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“…One of such SIMs which is a classical signal 3 cytokine with receptors expressed on T cells to enable them respond to shifts in their concentrations in the blood is IL-12. This cytokine, which has monocytes/macrophages, B cells, and dendritic cells as its established sources [35,36], is also critical for skewing CD4 T cell responses towards a T helper 1 (i.e., IFNγ hi , IL-4 low ) cytokine profile [37]. IL-12 secretion, together with many other SIMs, is known to be triggered and sustained during the immune activation that ensues in both the periphery and hepatic tissues during CHC.…”

Section: Discussionmentioning

confidence: 99%

HCC Immune Surveillance and Antiviral Therapy of Hepatitis C Virus Infection

et al. 2018

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Objective: HCV clearance by current antiviral therapies improves clinical outcomes but falls short in eliminating the risk for hepatocellular carcinoma (HCC) emergence. As the HCC immune surveillance establishment is vital for the control of neoplastic development and growth, we investigated its correlation with on-/post-treatment HCC emergence, and further analyzed the influence of viral eradication on this setup in patients with HCV-related liver cirrhosis. Design: PBMC isolated at baseline and longitudinally during therapy were analyzed for tumorassociated antigen (TAA)-specific CD8+ T cell responses against glypican-3 overlapping peptides in vitro using high-definition flow cytometry. Multianalyte profiling of fifty soluble inflammatory mediators (SIM) in the plasma was also performed using Luminex-based multiplex technology. Results: Cirrhosis patients were characterized by an altered profile of distinct SIMs at baseline. At this time point, immune-surveilling T cells targeting specific HCC-associated antigens were readily detectable in HCV-free cirrhosis patients whilst being rather weak in such patients who further developed HCC upon virus eradication. Therapy-induced cure of HCV infection analogously reduced the strength of the prevailing HCC immune surveillance machinery, particularly by CD8+ T cells in cirrhosis patients. These results were further vali- dated by T cell reactivities to six immuno-dominant HCC-associated HLA-A2-restricted epitopes. Further, we demonstrated that this phenomenon was likely orchestrated by alterations in SIMs -with evidence of IL-12 being a major culprit. Conclusion: Given the relationship between the baseline HCC-specific immune surveilling T cell responses and therapy-associated HCC emergence, and the impact of HCV clearance on its strength and magnitude, we recommend a continued HCC screening in cirrhotic HCV patients despite HCV resolution.

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Interleukin-12: An Update on its Immunological Activities, Signaling and Regulation of Gene Expression

Cited by 125 publications

References 221 publications

Wnt5a Skews Dendritic Cell Differentiation to an Unconventional Phenotype with Tolerogenic Features

Wnt5a Skews Dendritic Cell Differentiation to an Unconventional Phenotype with Tolerogenic Features

Role of Phosphatidylinositol-3 Kinase in Transcriptional Regulation of TLR-Induced IL-12 and IL-10 by Fcγ Receptor Ligation in Murine Macrophages

HCC Immune Surveillance and Antiviral Therapy of Hepatitis C Virus Infection

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