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-Activated Human Macrophages: Posttranslational Regulation by Pyrrolidine Dithiocarbamate1
*
Biochemistry and
Iron Groups, The Heart Research Institute, Camperdown, New South Wales, Australia; and
The Department of Pathology, University of Sydney, Sydney, New South Wales, Australia
Induction of the heme-containing indoleamine 2,3-dioxygenase (IDO)
by IFN-
is implicated in anti-microbial and pro-inflammatory
activities of human macrophages. Antioxidants can modulate the
expression of immune and inflammatory genes, and pyrrolidine
dithiocarbamate (PDTC) is a frequently used antioxidant to inhibit the
transcription factor NF-
B. Here we show that IFN- treatment of
human monocyte-derived macrophages (hMDMs) increased the proportion of
oxidized glutathione. PDTC attenuated this increase and inhibited IDO
activity, although it increased IDO protein expression and did not
affect IDO mRNA expression and enzyme activity directly. Other
antioxidants, 2-ME, ebselen, and t-butyl
hydroquinone, inhibited IDO protein expression. Similar to PDTC,
the heme biosynthesis inhibitor succinylacetone (SA) and the
iron-chelator pyridoxal isonicotinoyl hydrazone inhibited cellular IDO
activity without affecting protein expression, whereas addition of
hemin or the heme precursor 
-aminolevulinic acid increased IDO
activity. Also, incubation of IFN--activated hMDM with
-[14C]-aminolevulinic acid resulted in the
incorporation of label into immunoprecipitated IDO, a process inhibited
by PDTC and SA. Furthermore, supplementation of lysates from PDTC- or
SA-treated hMDM with hemin fully restored IDO activity to control
levels, and hemin also reversed the inhibitory action of SA but not
PDTC in intact cells. Together these results establish a requirement
for de novo heme synthesis for IDO activity in IFN--activated hMDM.
They show that, similar to other pro-inflammatory proteins, the
activity of IDO is modulated by antioxidants though in the case of PDTC
this takes place posttranslationally, in part by limiting the
availability of heme for the formation of
holo-IDO.
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