Carotenoid Uptake and Protection in Cultured RPE - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 335

15.11 BIOACTIVITIES OF CAROTENOIDS OTHER THAN
DIRECT ANTIOXIDANTS
Apart from their direct action as antioxidants, quenching electronically excited states and scaveng-
ing free radicals, carotenoids play many diverse roles in modulating inl ammatory, angiogenic,
apoptotic, and transcription pathways (Ben-Dor et al., 2005; Chew and Park, 2004; Chew et al.,
2003; Maccarrone et al., 2005; Santos et al., 1996, 1998; Selvaraj and Klasing, 2006; Selvaraj et al.,
2006; Sharoni et al., 2004; Sumantran et al., 2000). These various bioactivities have been investi-
gated in numerous studies in animals and in vitro on different cell types. Even though many of these
bioactivities are of great relevance for the retina, studies in that area are scarce. Next we shortly
discuss indirect carotenoid bioactivities focusing on those aspects which are particularly relevant to
the RPE and can be tested in vitro .
15.11.1 M ODULATION OF I NFLAMMATORY P ATHWAYS
RPE cells can express a number of anti-inl ammatory and pro-inl ammatory cytokines, and
complement factors constitutively and/or upon stimulation (Chen et al., 2007; Crane et al., 2000a;
Ebihara et al., 2007; Holtkamp et al., 2001; Joffre et al., 2007). Therefore the effects of carotenoids
on inl ammatory responses are of great relevance to the retina.
There is a growing body of evidence that carotenoids such as lutein and zeaxanthin exert potent
immunomodulatory effects in humans, animals, and in isolated macrophages (Chew and Park, 2004;
Ekam et al., 2006; Fuller et al., 1992; Hozawa et al., 2007; Izumi-Nagai et al., 2007; Jin et al., 2006;
Koutsos et al., 2007; Lidebjer et al., 2007; Santos et al., 1996, 1998; Seddon et al., 2006; Selvaraj
and Klasing, 2006; Selvaraj et al., 2006; Walston et al., 2006). Lutein has been shown to exert
anti-inl ammatory effects on endotoxin-induced uveitis in the rat by inhibiting the nuclear factor
(NF)-kB-dependent signaling pathway and the subsequent production of pro-inl ammatory media-
tors (Jin et al., 2006). An intravenous administration of lutein at doses of 10 mg/kg and 100 mg/kg
effectively prevents ini ltration of macrophages into the aqueous humor in the rat eye induced by
lipopolysaccharide, substantially inhibits activation of NF-kB responsible for production of some
inl ammatory cytokines, and reduces the expression of several markers of inl ammation, such as
nitric oxide, interleukin 6 (IL-6), monocyte chemotactic protein 1 (MCP-1), and tumor necrosis
factor a (TNF-a).
In the rat retina, ischemia upregulates expression of the neuronal nitric oxide synthase and
cyclo-oxygenase-2; these effects can be effectively inhibited by lutein (Choi et al., 2006).
Lutein can also effectively inhibit ini ltration of macrophages and upregulation of pro-
inl ammatory proteins, such as vascular endothelial growth factor, MCP-1, and intercellular adhe-
sion molecule-1 upon laser photocoagulation of a murine retina (Izumi-Nagai et al., 2007). In this
model the potent antiangiogenic action of lutein against choroidal neovascularization is probably
related to suppression of NF-kB pathway, including IkB-a degradation and p65 nuclear transloca-
tion (Izumi-Nagai et al., 2007).
Interestingly, opposing immunomodulatory effects can be observed using different carotenoid
concentrations, and the effects on up- or downregulation of the inl ammatory response by lutein can
be further modii ed by fatty acids (Selvaraj and Klasing, 2006; Selvaraj et al., 2006). For example,
it has been shown that lutein affects expression of inducible nitric oxide synthase (iNOS) in lipo-
saccharide-stimulated macrophages isolated from chickens or HD11 cells in vitro (Selvaraj et al.,
2006). At low concentration, 0.01 mM, lutein induces an upregulation of iNOS mRNA. Increasing
the concentration of lutein 10 times results in a downregulation of iNOS mRNA. The action of
lutein is modulated by eicosapentaenoate and, through the peroxisome proliferator activated recep-
tor g and retinoid X receptor (RXR) pathways, they can modulate iNOS expression in macrophages
(Rai and Shafaie, 2007; Selvaraj et al., 2006).