The Role of Stat4 in Species-Specific Regulation of Th Cell Development by Type I IFNs

Rogge, Lars; D’Ambrosio, Daniele; Biffi, Mauro; Penna, Giuseppe; Minetti, Lisa J.; Presky, David H.; Adorini, Luciano; Sinigaglia, Francesco

doi:10.4049/jimmunol.161.12.6567

Cited by 264 publications

(2 citation statements)

References 51 publications

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“…In addition to the P53 pathway, some immune-related pathways are activated in group C but inactivated in group B, such as the IFN-α response. The IFN-α pathway is activated in group B by promoting IL-21, IFN-γ, IL-15 in immune cells [ 31 – 33 ], and other cytokines in immune cells to drive the maturation of dendritic cells [ 34 ], which differentiate CD4 T cells into Th1 [ + 35 ] and increase the activation and cytotoxicity of CD8 T cells [ + 36 ]. IFN-α also mediates these immunomodulatory roles in the absence of intermediate cytokine production [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

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m6A-related lncRNA-based immune infiltration characteristic analysis and prognostic model for colonic adenocarcinoma

Wang

et al. 2023

Hereditas

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Background Colonic adenocarcinoma (COAD) is a common gastrointestinal tract tumor, and its occurrence and progression are typically associated with genomic instability, tumor-suppressor gene and oncogene mutations, and tumor mutational load. N6-methyladenosine (m6A) modification of RNAs and long non-coding RNA (lncRNA) expression are important in tumorigenesis and progression. However, the regulatory roles of m6A‐associated lncRNAs in the tumor microenvironment, stratification of prognosis, and immunotherapy are unclear. Methods We screened 43 prognostic lncRNAs linked to m6A and performed consistent molecular typing of COAD using consensus clustering. The single-sample Gene Set Enrichment Analysis and ESTIMATE algorithms were used to assess the immune characteristics of different subgroups. Covariation between methylation-related prognostic lncRNAs was eliminated by least absolute shrinkage and selection operator Cox regression. A nomogram was created and evaluated by combining the methylation-related prognostic lncRNA model with other clinical factors. The relationship between the prognostic model grouping and microsatellite instability, immunophenotype score, and tumor mutation burden was validated using R scripts. Finally, we used a linkage map to filter sensitive medicines to suppress the expression of high-risk genes. Three m6A-associated lncRNA modes were identified in 446 COAD specimens with different clinical endpoints and biological statuses. Risk scores were constructed based on the m6A-associated lncRNA signature genes. Patients with lower risk scores showed superior immunotherapy responses and clinical benefits compared to those with higher risk scores. Lower risk scores were also correlated with higher immunophenotype scores, tumor mutation burden, and mutation rates in significantly mutated genes (e.g., FAT4 and MUC16). Piperidolate, quinostatin, and mecamylamin were screened for their abilities to suppress the expression of high-risk genes in the model. Conclusions Quantitative assessment of m6A-associated lncRNAs in single tumors can enhance the understanding of tumor microenvironment profiles. The prognostic model constructed using m6A-associated lncRNAs may facilitate prognosis and immunotherapy stratification of patients with COAD; finally, three drugs with potential therapeutic value were screened based on the model.

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Section: Discussionmentioning

confidence: 99%

“…In addition to this, Perl scripts were used to calculate mutation frequency and variant/exon length (38 million) for each sample as a way to compared differences in tumor mutation load between clustered subtypes and risk score groupings [ 34 ]. And the “maftools” [ 35 ] R package was used to visualize the mutation types.…”

Section: Methodsmentioning

confidence: 99%

m6A-related lncRNA-based immune infiltration characteristic analysis and prognostic model for colonic adenocarcinoma

Wang

et al. 2023

Hereditas

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Cytokine regulation of IL-12 receptor β2 expression: differential effects on human T and NK cells

Gadina

Wang

et al. 2000

Eur. J. Immunol.

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IFN-α and IL-18 synergistically enhance IFN-γ production in human NK cells: differential regulation of Stat4 activation and IFN-γ gene expression by IFN-α and IL-12

et al. 2001

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IFN‐γ , a product of NK and T cells, is a key cytokine contributing innate and adaptive immunity. IFN‐γ production is induced via direct cell‐cell contacts with APC and IFN‐γ ‐producing cells or by cytokines. During microbial infections macrophage‐derived IFN‐α , IL‐12, and IL‐18 enhance IFN‐γ production and Th1 response. Here we show that IFN‐α in combination with IL‐18 very efficiently induces IFN‐γ expression also in primary, nonactivated NK cells and in NK‐92 cell line. Comparison of the kinetics of IFN‐γ mRNA expression in nonactivated NK cells, NK‐92 cells and activated T cells stimulated with IFN‐α or IL‐12 revealed that, although both of these cytokines directly up‐regulate IFN‐γ mRNA expression, its levels remain elevated much longer with IL‐12 stimulation. In both NK cells and T cells, Stat4 is known to be critical in IL‐12 and IFN‐α signaling. We show that Stat4 activation is transient in cells stimulated with IFN‐α , whereas IL‐12 induces more long‐lasting activation of the transcription factor. This prolonged activation of IFN‐γ gene by IL‐12 may result in more efficient IFN‐γ production compared to that of IFN‐α . Our results demonstrate that IFN‐α and IL‐18 are important innate cytokines in inducing NK cell IFN‐γ production.

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The Role of Stat4 in Species-Specific Regulation of Th Cell Development by Type I IFNs

Cited by 264 publications

References 51 publications

m6A-related lncRNA-based immune infiltration characteristic analysis and prognostic model for colonic adenocarcinoma

m6A-related lncRNA-based immune infiltration characteristic analysis and prognostic model for colonic adenocarcinoma

Cytokine regulation of IL-12 receptor β2 expression: differential effects on human T and NK cells

IFN-α and IL-18 synergistically enhance IFN-γ production in human NK cells: differential regulation of Stat4 activation and IFN-γ gene expression by IFN-α and IL-12

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