ArticleThe Journal of biological chemistry2013
The p40 subunit of interleukin (IL)-12 promotes stabilization and export of the p35 subunit: implications for improved IL-12 cytokine production.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 78 citations in OpenAlex.
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- The subunits of IL-12, originating from two distinct cells, can functionally synergize to protect against pathogen dissemination in vivo.Cell reports · 2021Article
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- A Chaperone-Like Role for EBI3 in Collaboration With Calnexin Under Inflammatory Conditions.Frontiers in immunology · 2021Review
- IL-12 and IL-23-Close Relatives with Structural Homologies but Distinct Immunological Functions.Cells · 2020Review
- SNPs in the interleukin-12 signaling pathway are associated with breast cancer risk in Puerto Rican women.Oncotarget · 2020Article
- IL-23 Promotes a Coordinated B Cell Germinal Center Program for Class-Switch Recombination to IgG2b in BXD2 Mice.Journal of immunology (Baltimore, Md. : 1950) · 2020Article
- Site-Specific Protein Labeling with Fluorophores as a Tool To Monitor Protein Turnover.Chembiochem : a European journal of chemical biology · 2020Article
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
Abstract
IL-12 is a 70-kDa heterodimeric cytokine composed of the p35 and p40 subunits. To maximize cytokine production from plasmid DNA, molecular steps controlling IL-12p70 biosynthesis at the posttranscriptional and posttranslational levels were investigated. We show that the combination of RNA/codon-optimized gene sequences and fine-tuning of the relative expression levels of the two subunits within a cell resulted in increased production of the IL-12p70 heterodimer. We found that the p40 subunit plays a critical role in enhancing the stability, intracellular trafficking, and export of the p35 subunit. This posttranslational regulation mediated by the p40 subunit is conserved in mammals. Based on these findings, dual gene expression vectors were generated, producing an optimal ratio of the two subunits, resulting in a ~1 log increase in human, rhesus, and murine IL-12p70 production compared with vectors expressing the wild type sequences. Such optimized DNA plasmids also produced significantly higher levels of systemic bioactive IL-12 upon in vivo DNA delivery in mice compared with plasmids expressing the wild type sequences. A single therapeutic injection of an optimized murine IL-12 DNA plasmid showed significantly more potent control of tumor development in the B16 melanoma cancer model in mice. Therefore, the improved IL-12p70 DNA vectors have promising potential for in vivo use as molecular vaccine adjuvants and in cancer immunotherapy.
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