Pathophysiological Consequences of Protein N-Homocysteinylation - Homocysteine in Protein Structure/Function and Human Disease - page 112

chronic expression of the inflammatory cytokines and chemokines can be harmful
and lead to a disease. Numerous studies have established a link between
hyperhomocysteinemia and innate immune responses. For example, in humans,
TNF-

, a key cytokine in the inflammatory process, is strongly correlated with
plasma tHcy (r ¼

α

0.001), and in multivariate regression analysis, plasma
tHcy is an independent predictor of the plasma TNF-a levels [380].
Other evidence also suggests that Hcy contributes to innate immune responses.
Indeed, many human studies, although not all [381-384], have reported
associations between Hcy and markers of inflammation. For example, significant
associations between plasma tHcy and CRP are observed in the Framingham Heart
Study [385] and in the Physician's Health Study [386]. In another study,
hyperhomocysteinemia is associated with increased levels of both CRP and inter-
leukin-6 in humans [387]. A similar positive association between Hcy and interleu-
kin-6 is reported in patients with diabetic nephropathy [388]. Importantly, in the
Holven et al. study [387], elevated level of interleukin-6 is observed in hyperhomo-
cysteinemic individuals in the absence of hypercholesterolemia. Plasma tHcy is
positively associated with soluble tumor necrosis factor (TNF) receptor in the
Nurses' Health Study [389]. A positive correlation is also observed between plasma
tHcy and neopterin (a marker of Th1 type immune response) in Parkinson's disease
patients [390].
Furthermore, dietary hyperhomocysteinemia is known to trigger an innate
immune response and enhance vascular inflammation in mice [45]. This is
manifested by increased activation of nuclear factor (NF)-

0.48, p <

B in the aorta and
kidney, enhanced expression of vascular cell adhesion molecule (VCAM)-1 and
receptor for advanced glycation end products in the aorta, and TNF-

κ

in plasma
[45]. Elevated Hcy is associated with elevated monocyte chemotactic protein-1 and
increased expression of vascular adhesion molecules in humans [391, 392] and rats
[393-395].
Genetic hyperhomocysteinemia in untreated or poorly compliant human CBS-
deficient patients leads to chronic induction (3.7- to 72-fold) of multiple
proinflammatory cytokines [IL-1α, IL-6, TNF-α, Il-17, and IL-12(p70)] and che-
motactic chemokines (fractalkine, MIP-1α, and MIP-1β) compared to the normal
age- and gender-matched controls [396]. Hcy-lowering therapy normalizes the
levels of proinflammatory cytokines and chemokines, with the exception of TNF-
α

α

, which, although reduced 3.4-fold by the therapy, remained tenfold elevated
above the normal level.
Similarly, hyperhomocysteinemic Cbs / mice exhibit a chronic inflammatory
state as indicated by measurements of plasma CRP: Cbs / mice have sevenfold
elevated CRP, compared with wild-type littermates. Hcy lowering by betaine
treatment significantly reduced plasma CRP levels (by 50 %), although it remained
elevated compared with control wild-type mice. In addition, Cbs / mice have
highly elevated proinflammatory cytokines Il-1 α , Il-1beta (three to fourfold), and

TNF- (35-fold). Hcy lowering significantly ameliorated the constitutive expres-

sion of proinflammatory cytokines in Cbs / mice [396].

α