Lipopolysaccharide, IFN-γ, and IFN-β induce expression of the thiol-sensitive ART2.1 ecto-ADP-ribosyltransferase in murine macrophages

Shiyuan Hong, Anette Brass, Michel Seman, Friedrich Haag, Friedrich Koch-Nolte, George R. Dubyak

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Nicotinamide adenosine dinucleotide (NAD) can act as a modulator of multiple immune and inflammatory responses when released into extracellular compartments. These actions of extracellular NAD are largely mediated by a family of mammalian ecto-ADP-ribosyltransferases (ARTs) that covalently modify target extracellular or cell surface proteins by transferring ADP-ribose to arginine or cysteine residues. In this study, we report that bone marrow-derived macrophages (BMDM) from BALB/c mice lack constitutive expression of any of the six murine ecto-ART subtypes, but selectively up-regulate ART2.1 in response to multiple proinflammatory mediators including agonists for TLR and type I and type II IFN. Stimulation of BMDM with LPS, IFN-β, or IFN-γ induced high expression of ART2.1, but not ART2.2, as a GPI-anchored cell surface ectoenzyme. ART2.1 expression in response to LPS was potentiated by inhibition of ERK1/2 signaling, but inhibited by blockade of the NF-κB, PI3K, and JAK-STAT pathways or the presence of neutralizing anti-IFN-β. The catalytic function of the induced cell surface ART2.1 was strictly dependent on the presence of extracellular thiol-reducing cofactors, suggesting that in vivo activity of ART2.1-expressing macrophages may be potentiated in hypoxic or ischemic compartments. Consistent with the mutated art2a gene in C57BL/6 mice, LPS- or IFN-stimulated BMDM from this strain lacked expression of cell surface ART2 activity in the presence or absence of extracellular thiol reductants. Collectively, these studies identify ART2.1 as a new candidate for linking autocrine/paracrine activation of inflammatory macrophages to the release of NAD, a critical intracellular metabolite.

Original languageEnglish (US)
Pages (from-to)6215-6227
Number of pages13
JournalJournal of Immunology
Volume179
Issue number9
StatePublished - Nov 1 2007

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Hong, S., Brass, A., Seman, M., Haag, F., Koch-Nolte, F., & Dubyak, G. R. (2007). Lipopolysaccharide, IFN-γ, and IFN-β induce expression of the thiol-sensitive ART2.1 ecto-ADP-ribosyltransferase in murine macrophages. Journal of Immunology, 179(9), 6215-6227.