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Interleukin-1ßces Human Endothelial Surface Expression and Trans-presentation of Interleukin-15 by Relieving let-7c-3p Suppression of Protein Translation (small RNA-Seq)

ABSTRACT: Expression of interleukin-15 (IL-15) on the surface of human graft endothelial cells (ECs) bound to the IL-15 receptor a (IL-15Ra) subunit can increase the activation of cytotoxic T lymphocytes (CTLs), potentiating allograft rejection. Our previous work showed that surface expression of this protein complex could be induced by alloantibody-mediated complement activation through increased IL-1b synthesis, secretion, and autocrine/paracrine IL-1-mediated activation of NF-kB. Here we report that cultured human ECs express 8 differently spliced IL-15 transcripts. Remarkably, IL-1β does not alter the expression level of any IL-15 transcript but induces surface expression independently of RNA Polymerase II-mediated transcription while requiring new protein translation. Mechanistically, IL-1β causes an NF-kB-mediated reduction in the level of microRNA Let-7c-3p, thereby relieving a block of translation of IL-15 surface protein. Let7c-3p antimir can induce EC surface expression of IL-15/IL-15Ra in the absence of complement activation or of IL-1, enabling IL-15 trans-presentation to boost CD8 T cell activation. Because of the complexity we have uncovered in IL-15 regulation, we recommend caution in interpreting increased total IL-15 mRNA or protein levels as a surrogate for trans-presentation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266373 | GEO | 2024/09/30

REPOSITORIES: GEO

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Interleukin-1β Induces Human Endothelial Surface Expression and Trans-presentation of Interleukin-15 by Relieving let-7c-3p Suppression of Protein Translation (bulk RNA-Seq)

Project description:Expression of interleukin-15 (IL-15) on the surface of human graft endothelial cells (ECs) bound to the IL-15 receptor a (IL-15Ra) subunit can increase the activation of cytotoxic T lymphocytes (CTLs), potentiating allograft rejection. Our previous work showed that surface expression of this protein complex could be induced by alloantibody-mediated complement activation through increased IL-1b synthesis, secretion, and autocrine/paracrine IL-1-mediated activation of NF-kB. Here we report that cultured human ECs express 8 differently spliced IL-15 transcripts. Remarkably, IL-1β does not alter the expression level of any IL-15 transcript but induces surface expression independently of RNA Polymerase II-mediated transcription while requiring new protein translation. Mechanistically, IL-1β causes an NF-kB-mediated reduction in the level of microRNA Let-7c-3p, thereby relieving a block of translation of IL-15 surface protein. Let7c-3p antimir can induce EC surface expression of IL-15/IL-15Ra in the absence of complement activation or of IL-1, enabling IL-15 trans-presentation to boost CD8 T cell activation. Because of the complexity we have uncovered in IL-15 regulation, we recommend caution in interpreting increased total IL-15 mRNA or protein levels as a surrogate for trans-presentation.

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