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, and IFN-
Induce Expression of the Thiol-Sensitive ART2.1 Ecto-ADP-Ribosyltransferase in Murine Macrophages1
* Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44120;
Institut National de la Santé et de la Recherche Médicale Unité 519, University of Rouen, Rouen, France; and
Institute of Immunology, University Hospital, Hamburg, Germany
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-
, or IFN-
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-
B, PI3K, and JAK-STAT pathways or the presence of neutralizing anti-IFN-. 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported Grant GM36387 (to G.R.D.) from the National Institutes of Health and Grant No. 310/6 (to F.H. and F.K.-N.) from The Deutsche Forschungsgemeinschaft.
2 Address correspondence and reprint requests to Dr. George R. Dubyak, Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44120. E-mail address: george.dubyak{at}case.edu
3 Abbreviations used in this paper: NAD, nicotinamide adenosine dinucleotide; ART, ADP-ribosyltransferase; BMDM, bone marrow-derived macrophage; NZW, New Zealand White; PI-PLC, phosphatidylinositol phospholipase C; IRF, IFN response factor; iNOS, inducible NO synthase.
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