Molecular Immunology 45 (2008) 235–243
Interleukin-13 primes iNO synthase expression induced
by LPS in mouse peritoneal macrophages
Authier H
´
el
`
ene
a
, Sophie Cassaing
a,b,∗
, Agn
`
es Coste
a
, Patricia Balard
a
, Amandine Gales
a
,
Antoine Berry
a,b
,Val
´
erie Bans
a
, Marie-H
´
el
`
ene Bessi
`
eres
a,b
, Bernard Pipy
a,∗∗
a
Laboratoire des macrophages, M´ediateurs de l’Inflammation et Interactions Cellulaires, Universit´e Paul Sabatier Toulouse III,
EA2405, INSERM IFR31 BP84225, 31432 Toulouse, Cedex 4, France
b
D´epartement de Parasitologie Mycologie, Centre Hospitalier Universitaire Hˆopital Rangueil 1 avenue
Jean Poulh`es 31403 Toulouse Cedex 4, France
Received 16 January 2007; received in revised form 2 April 2007; accepted 6 April 2007
Available online 12 June 2007
Abstract
Th2 cytokines such as interleukin-13 (IL-13) have both, stimulatory and inhibitory effects on effectorfunctions of macrophages. Reactive nitrogen
species are classicaly induced in Th1 cytokines and/or lipopolysaccharides (LPS) activated macrophages and this response is inhibited by IL-13.
In contrast, IL-13 primes macrophages to produce NO in response to LPS when IL-13 treatment happens prior to LPS exposure. This mechanism
occurs through a complex signalling pathway, which involves the scavenger receptor CD36, the LPS receptor CD14 and the nuclear receptor
PPAR␥. The enhancement of NO production is the consequence of iNOS induction at mRNA and protein levels. The increase of the NO production
induced by LPS in IL-13 pre-treated macrophages is found to potentiate the inhibition of Toxoplasma gondii intracellular replication. These results
reveal a novel IL-13 signalling pathway that primes the antimicrobial activity of macrophages induced by LPS caused by overexpression of the
iNOS-NO axis.
© 2007 Elsevier Ltd. All rights reserved.
Keywords: Peroxisome Proliferator Activated Receptor g; PPARg ligands; 15-Deoxy-delta prostaglandin J2; CD36; CD14; Interleukin 13; Macrophage; Inducible
nitric oxide synthase
1. Introduction
Macrophages have got a pivotal role in innate immune
defence against microbial infections. The classical activation
of macrophages and particularly the inducible form of NO
synthase (iNOS) is induced by Th1 cytokines or microbial endo-
toxins (Gordon, 2003). Th1 cytokines and endotoxins have a
synergistic action. Thus, IFN-␥ pre-treatment referred to as a
priming effect increases the magnitude and the sensitivity of the
induction of iNOS expression and activity by LPS. In mouse
macrophages, iNOS is responsible for the increased production
∗
Corresponding author at: Laboratoire des macrophages, M
´
ediateurs de
l’Inflammation et Interactions Cellulaires, Universit
´
e Paul Sabatier Toulouse
III, EA2405, INSERM IFR31 BP84225, 31432 Toulouse, Cedex 4, France.
Tel.: +33 5613 22892; fax: +33 5613 22096.
∗∗
Corresponding author.
E-mail addresses: cassaing.s@chu-toulouse.fr (S. Cassaing),
pipy@toulouse.inserm.fr (B. Pipy).
of NO through an oxidation of l-arginine to l-citrulline. Among
the macrophages-derived effector molecules, NO is a key cyto-
toxic factor for microbicidal (Bohne et al., 1994; Elgun et al.,
2005; Hazlett et al., 2005; Khan et al., 1996; Liew et al., 1990)
and tumoricidal processes (Lechner et al., 2005).
Interleukin-13 (IL-13) was originally described as a T cell-
derived cytokine with pleiotropic effects. The known effector
functions of IL-13 continues to grow and includes a diverse array
of biological activities including resistance to gastrointestinal
nematodes, regulation of intracellular parasitism, inflammatory
diseases of the lung and cancer (Wynn, 2003). In general,
Th2 cytokines are described to be able to down-modulate the
macrophage production of NO and inflammatory activity (IL-12,
TNF-␣)(Bogdan et al., 1994; Doherty et al., 1993). They control
the overproduction of inflammatory mediators, potentially dele-
terious to host survival. This phenomenon is observed further to
the classical Th1 response against pathogens such as Toxoplasma
gondii (Roberts et al., 1996; Suzuki et al., 2000b). The classi-
cal down-regulation of the NO production by IL-13 or IL-4 is
0161-5890/$ – see front matter © 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.molimm.2007.04.007