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Jialal, 2000a). Monocytes release IL-6 under
hyperglycemic conditions, which seems to be
mediated through the upregulation of PKC-a
and PKC-b (Jeschke et al ., 2002). In addition
to PKC-a and PKC-b, IL-6 is regulated by p38
mitogen-activated protein kinase (MAPK) and
NFkB; both of which impair IL-6 release upon
inhibition (Devaraj et al ., 2005). Likewise,
inhibiting COX-2 activation and prostaglandin
E 2 (PGE 2 ) formation ameliorates IL-6 produc-
tion (Williams and Shacter, 1997). In summary,
IL-6 is regulated by PKC, p38MAPK, NFkB,
COX-2 and/or PGE 2 , all of which are modu-
lated by a-tocopherol (Boscoboinik et al ., 1991;
Tasinato et al ., 1995; Wu et al ., 1998; Venugopal
et al ., 2002; Egger et al ., 2003; Devaraj and Jialal,
2005; Devaraj et al ., 2005).
Immune system dysfunction is a conse-
quence of ageing, and IL-2 is routinely meas-
ured to identify immune system dysfunction
in the elderly (Nagel et al ., 1988; Rink et al .,
1998). IL-2 augments T-lymphocyte prolif-
eration in response to antigenic stimulation,
including the generation of cytotoxic and
suppressor T cells (Waldmann, 1989; Nakarai
et al ., 1994). Thus, impaired IL-2 production or
secretion hinders specific immune responses.
Previous studies have investigated the influ-
ence of supplemental vitamin E on IL-2 in
the elderly (Meydani et al ., 1990; Pallast et al .,
1999). It has been shown that, in the elderly,
vitamin E supplementation increases a-toco-
pherol concentrations in the plasma and in
peripheral blood mononuclear cells (Table 6.1;
Meydani et al ., 1990). The increase in vitamin
E occurred concomitantly with IL-2 increases
and PGE 2 decreases (Meydani et al ., 1990).
Likewise, in experimental rats, vitamin E sup-
plementation decreased macrophage COX
activity and PGE 2 production (Wu et al ., 1998).
These are interesting results because increased
COX-2 expression induces PGE 2 production
(Hayek et al ., 1997) and could contribute to
the age-associated IL-2 decrease (Walker
et al ., 1983; Beharka et al ., 1997). Moreover,
inhibiting COX-2 expression and PGE 2 pro-
duction increases IL-2, thereby identifying a
potential mechanism or source of IL-2 regula-
tion by vitamin E. An alternative explanation
of IL-2 regulation could relate to the antioxi-
dant property of vitamin E. Specifically, lipid
hydroperoxides and reactive nitrogen species
regulate COX activation (Hemler and Lands,
1980; Fujimoto et al ., 2004). It is feasible that
the peroxyl radical and reactive nitrogen
scavenging properties of vitamin E (a- and
g-tocopherol forms) attenuate COX activity
and increase IL-2. None the less, these results
indicate that vitamin E regulates IL-2 produc-
tion by modulating eicosanoid synthesis and,
in theory, by scavenging reactive oxygen and
nitrogen species.
On the basis of the inconsistency and vari-
ability of available data (Meydani et al ., 1990;
Pallast et al ., 1999; Wu et al ., 2007), it is postulated
that the cytokine-modulating property of vita-
min E could be genetically determined. To inves-
tigate this question, Belisle et al . (2009) examined
the interaction between vitamin E and a single
nucleotide polymorphism on TNF-a produc-
tion in the elderly. In elderly nursing home
subjects treated with vitamin E, TNF-a produc-
tion was lower in those with the A/A and A/G
genotype at TNF-a -308G
A than those with
the A allele treated with the placebo (Belisle
et al ., 2009). The original results provided by
Belisle et al . (2009) identify that the influence of
supplemental vitamin E on TNF-a production
is genetically determined and provide a possi-
ble explanation on why previous studies found
a null effect of vitamin E on TNF-a. In a subse-
quent study, Belisle et al . (2010) investigated the
influence of cytokine gene polymorphisms on
respiratory tract infection and response to vita-
min E in nursing home patients. In women who
received supplemental vitamin E, the G/G gen-
otype at IL-10 -819G
A was associated with a
decreased incidence of lower respiratory tract
infections, whereas the A/A genotype at IL-10-
A displayed more lower respiratory
tract inflections than those who received a pla-
cebo treatment (Belisle et al ., 2010). These results
not only suggest that the development of respi-
ratory tract infections in nursing home patients
is influenced by supplemental vitamin E, but
again establish that a single nucleotide poly-
morphism is influential on the response to sup-
plemental vitamin E outcomes.
g -Tocopherol
g-Tocopherol is another form of vitamin E that
possesses antioxidant and anti-inflammatory
properties. g-Tocopherol traps reactive nitrogen
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