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Type I interferons and IL-12: convergence and cross-regulation among mediators of cellular immunity.

TitleType I interferons and IL-12: convergence and cross-regulation among mediators of cellular immunity.
Publication TypeJournal Article
Year of Publication2001
AuthorsByrnes AA, Ma X, Cuomo P, Park K, Wahl L, Wolf SF, Zhou H, Trinchieri G, Karp CL
JournalEur J Immunol
Volume31
Issue7
Pagination2026-34
Date Published2001 Jul
ISSN0014-2980
KeywordsCells, Cultured, DNA-Binding Proteins, Down-Regulation, Humans, Immunity, Cellular, Interferon-alpha, Interferon-beta, Interleukin-10, Interleukin-12, Macrophages, Monocytes, Monokines, Promoter Regions, Genetic, Proto-Oncogene Proteins, Response Elements, RNA, Messenger, Trans-Activators, Transcription, Genetic
Abstract

Therapeutic use of type I IFN (IFN-alpha/beta) has become common. Many of the diverse diseases targeted are marked by pathogenetic abnormalities in cell-mediated immunity (CMI), these cellular immune responses either causing injury to the host, lacking sufficient vigor for virus or tumor clearance, or both. In general, therapeutic efficacy is limited. It is thus notable that the pleiotropic effects of type I IFN on CMI remain poorly understood. We characterized the effects of type I IFN on the production of IL-12, the central immunoregulatory cytokine of the CD4(+) T cell arm of CMI. We show that type I IFN are potent inhibitors of IL-12 production by human monocytes/macrophages. The underlying mechanism involves transcriptional inhibition of the IL-12p40 gene, marked by down-regulation of PU.1 binding activity at the upstream Ets site of the IL-12p40 promoter. Type I IFN have previously been shown to be able to substitute for IL-12 in driving IFN-gamma production from T and NK cells. The ability of IFN-alpha/beta to suppress IL-12 production while up-regulating IFN-gamma production suggests a possible mechanistic basis for the difficulties of employing these cytokines in diseases involving abnormalities of CMI.

DOI10.1002/1521-4141(200107)31:7<2026::aid-immu2026>3.0.co;2-u
Alternate JournalEur J Immunol
PubMed ID11449355
Grant ListAI45899 / AI / NIAID NIH HHS / United States
DK56415 / DK / NIDDK NIH HHS / United States
NS39435 / NS / NINDS NIH HHS / United States

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