Macrophage biology and immunology: man is not a mouse
Markus Schneemann1 and Gabriele Schoeden
Department of Medicine, University Hospital of Zürich, Zürich, Switzerland
A recent article by Shibata et al. [1] and an interview with
the senior investigator Kobayashi [2], both in the October
2006 issue of Journal of Leukocyte Biology, discuss the role
of macrophage-derived NO in the clearance of apoptotic
cells. We were surprised that neither in the original paper
nor in the accompanying interview was it discussed that
these results rely entirely on data obtained in murine mac-
rophages. It is, however, evident that there are differences
in macrophage NO production and regulation among differ-
ent species [3, 4]. Several years ago, we and others [5–7]
described fundamental differences between macrophages
from mice and humans regarding NO synthase (NOS) activ-
ity. Murine macrophages produce large amounts of NO and
L-citrulline from L-arginine via induction of the inducible
form of NOS (iNOS). In parallel, murine macrophages syn-
thesize the obligatory cofactor tetrahydrobiopterin (BH4),
essential for stabilization and function of the iNOS enzyme
protein [8, 9]. Human as well as macrophages from other
animal species, such as rabbits, goats, or Syrian hamsters,
do not have NOS activity nor do they synthesize BH4 [7, 10,
11]. In addition, murine macrophages consume most of the
L-arginine by another enzyme—arginase—and convert it
into L-ornithine. This arginase is not active in human mac-
rophages too [7, 9, 12]. A lot of research has since been
done to demonstrate nitrite production in human macro-
phages. Recent reviews claim that human macrophages have
iNOS activity, albeit induced by other stimuli rather than
those inducing nitrite production in murine macrophages
[13]. We evaluated several of these stimuli and could show
that nitrite was not produced by iNOS activity in human
macrophages. The nitrite measured came from other non-
cellular sources [14]. None of the articles cited as proof for
iNOS activity in human macrophages provides sound bio-
chemical data about L-arginine consumption, BH4 synthe-
sis, and L-citrulline production [13]. Moreover, they do not
control for nitrite generation from other nonmacrophage
sources [14]. The only report that demonstrates nitrite pro-
duction from NOS activity in human macrophage-like cells
is an article by Bertholet et al. [15]. There, the U937
monoblastic leukemia cell line was transfected with a plas-
mid containing a functional iNOS gene. Nitrite production
by these cells, however, totally depended on substitution of
the cofactor BH4 and additional substrate [15]. As species
differences are not confined to NOS activity and are funda-
mental in many aspects of immunology [3, 16, 17], we propose
that the species involved should be mentioned in the title and
abstract of articles dealing with common aspects of immunity.
Key Words: nitric oxide 䡠 species differences 䡠 NO synthase
䡠 arginase
0741-5400/07/0081-579 © Society for Leukocyte Biology
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1
Correspondence: Department of Medicine, University Hospital of Zürich,
Raemistrasse 100, Zürich CH-8091, Switzerland. E-mail: schneema@yahoo.com
Received November 28, 2006; revised December 4, 2006; accepted Decem-
ber 4, 2006.
doi: 10.1189/jlb.1106702
Journal of Leukocyte Biology Volume 81, March 2007 579