Carotenoid Uptake and Protection in Cultured RPE - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 336

Also degradation products of carotenoids exhibit immunomodulatory effects. For example,
b-carotene degradation products can stimulate production of superoxide by activated neutrophils at
low micromolar concentrations but exhibit inhibitory effects at concentrations above 20 mM (Siems
et al., 2003).
Considering the propensity of RPE cells to express a range of anti-inl ammatory and pro-
inl ammatory proteins, the proven role of inl ammation in uveitis and AMD, as well as potent
immunomodulatory effects of carotenoids, it is of importance to determine the immunomodulatory
effects of carotenoids and their degradation products in the RPE.
15.11.2 R EMODELING OF E XTRACELLULAR M ATRIX
Expression of matrix metalloproteinases (MMPs) and their inhibitors is an important function of
the RPE, particularly with respect to the maintenance of appropriate permeability of the Bruch's
membrane (Ahir et al., 2002). This function can be tested in vitro (Marin-Castano et al., 2006). For
example, it has been shown that the expression of MMP-2, TIPM-2s (tissue inhibitor of MMP-2),
and type IV collagen by cultured ARPE-19 cells is affected by repetitive exposures to nonlethal
oxidant injury with hydroquinone (Marin-Castano et al., 2006). Oxidative stress decreases MMP-2
activity and increases collagen type IV accumulation.
It has been demonstrated in other cell types that lutein can inhibit expression of MMPs and/
or activity (Philips et al., 2007). For example, in dermal i broblasts lutein inhibits expression of
MMP-1 and decreases levels of MMP-2 protein (Philips et al., 2007). In melanoma cells, lutein
inhibits MMP-1 expression while stimulating TIMP-2 (Philips et al., 2007). Moreover it has been
shown that lutein inhibits elastin expression in i broblasts subjected to oxidative stress by exposure
to ultraviolet light (Philips et al., 2007). These results clearly indicate that lutein can play an impor-
tant role in remodeling of the extracellular matrix.
Therefore it is of interest to determine whether carotenoids can modulate the turnover of the
extracellular matrix by the RPE by affecting the expression of MMPs, elastin, and/or collagen.
Cultured RPE cells are a suitable model for such investigations.
15.11.3 M ODULATION OF L IPID M ETABOLISM AND T RANSPORT
Interestingly, it has been shown that supplementation of greeni nches with lutein and zeaxanthin at a
ratio of 20:1 increases plasma levels of triglycerides and bird body mass (Horak et al., 2006). These
data suggest that xanthophylls may affect lipid metabolism.
Another indication of involvement of certain xanthophylls in lipid metabolism comes from
studies on macrophages in vitro . Supplementation of macrophages with lutein or b-cryptoxanthin
has been found to upregulate the lipid transporter ABCA1 expression (Matsumoto et al., 2007).
ABCA1 expression is regulated at the transcriptional level by the liver X receptors, RXR, and
retinoic acid receptor (RAR) (Costet et al., 2003; Koldamova et al., 2003; Venkateswaran et al.,
2000). These receptors have been known to be activated by ligands such as 22( R )-hydroxycholes-
terol, 9- cis -retinoic acid, and all- trans -retinoic acid (Costet et al., 2003; Koldamova et al., 2003;
Venkateswaran et al., 2000). It has been recently determined that b-cryptoxanthin and lutein, but
not b-carotene, zeaxanthin, astaxanthin, or lycopene can serve as ligands for RAR (Matsumoto
et al., 2007). Moreover, it has been shown that b-cryptoxanthin can upregulate ABCA1 and
ABCG1 expression in macrophages and this effect is inhibited by the RAR pan-antagonist, LE540
(Matsumoto et al., 2007).
As the RPE plays an important role in lipid metabolism and regulation of dynamic transport
between the choriocapillaris and photoreceptors, it is important to determine whether carotenoids
affect these pathways in the RPE.