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Transcriptional suppression of interleukin-12 gene expression following phagocytosis of apoptotic cells.

TitleTranscriptional suppression of interleukin-12 gene expression following phagocytosis of apoptotic cells.
Publication TypeJournal Article
Year of Publication2004
AuthorsKim S, Elkon KB, Ma X
JournalImmunity
Volume21
Issue5
Pagination643-53
Date Published2004 Nov
ISSN1074-7613
KeywordsApoptosis, Cell Communication, Cells, Cultured, Humans, Interleukin-12, Interleukin-12 Subunit p35, Phagocytosis, Phosphorylation, Promoter Regions, Genetic, Protein Subunits, Repressor Proteins, RNA, Messenger, Transcription, Genetic, Transforming Growth Factor beta, Transforming Growth Factor beta1
Abstract

Phagocytosis of apoptotic cells usually results in an anti-inflammatory state with inhibition of proinflammatory cytokines such as IL-12. How apoptotic cell-derived signals regulate IL-12 gene expression is not understood. We demonstrate that cell-cell contact with apoptotic cells is sufficient to induce profound inhibition of IL-12 production by activated macrophages. Phosphatidylserine could mimic the inhibitory effect. The inhibition does not involve autocrine or paracrine actions of IL-10 and TGF-beta. We report the identification, purification, and cloning of a novel zinc finger nuclear factor, named GC binding protein (GC-BP), that is induced following phagocytosis of apoptotic cells by macrophages or by treatment with phosphatidylserine. GC-BP selectively inhibits IL-12 p35 gene transcription by binding to its promoter in vitro and in vivo, thus decreasing IL-12 production. Blocking GC-BP by RNA interference restores IL-12 p35 transcription and IL-12 p70 synthesis. Finally, GC-BP itself undergoes functionally significant tyrosine dephosphorylation in response to apoptotic cells.

DOI10.1016/j.immuni.2004.09.009
Alternate JournalImmunity
PubMed ID15539151
Grant ListAI45899 / AI / NIAID NIH HHS / United States

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