Arginine is a semiessential amino acid in healthy adult human, but is
essential for preterm, newborn or critically ill patients. Arginine can
be supplied from our diet or de novo synthesis from citrulline. In
conditions of sepsis or endotoxemia, arginine may be deficient and be
accompanied with altered immune response. L-arginine supplementation can
ameliorate dysregulated immune condition and improve prognosis. Many
studies had tried L-arginine or L-citrulline supplementation to examine
the effect on immune response in the adult population. Few had studied
on the young children. In this study, we determined the effect of
L-arginine and L-citrulline supplementation on the immune response of
infantile rats. Male infantile rats received normal saline, L-arginine
(200 mg/kg/day) or L-citrulline (200 mg/kg/day) intraperitoneally over
postnatal day 8 to day 14. The infantile rats were then sacrificed. The
blood was analyzed while the spleen was indicated for immune analysis
after stimulation with concanavalin A (Con A) or lipopolysaccharide
(LPS). We found L-arginine supplementation enhanced Th1 immune response
by increasing IFN-γ production. Both the L-arginine and L-citrulline
therapy can modulate regulatory T-cell (Treg) immune effects by
increasing the IL-10 level. Only the L-citrulline group showed a TGF-β1
increase. Both L-arginine and L-citrulline therapy were also noted to
decrease SMAD7 expression and enhance SIRT-1 abundance. However, FOXP3
expression was only modulated by L-citrulline treatment. We then
concluded that L-arginine and L-citrulline supplementation can modulate
the regulatory T-cells function differently for infantile rats.wisepoqder L(+)-Arginine
Introduction
Arginine is a semi-essential amino acid in human depending on the
developmental stage or health status of the individual. Arginine can be
derived from dietary intake, from de novo synthesis from citrulline and
through protein breakdown. It is essential to preterm, newborn or
critically ill patients, as preterm/newborns are unable to synthesize
arginine, while critical ill patients' arginine are often depleted (1).
Arginine has many important roles in several metabolic pathways. For
immune system, its deficiency is associated with sepsis and inflammatory
conditions (2–5). Arginine deficiency is related to decreased arginine
uptake and impaired arginine de novo synthesis from citrulline, in
combination with an enhanced arginine catabolism by the up-regulation of
arginase and the nitric oxide synthase (NOs) in the immune response
(6). Arginase and NOs can be induced by cytokines produced by T helper
cells. NOs is stimulated by Th1 cytokines such as interferon-gamma
(IFN)-γ and interleukin (IL)-1 which play important roles in
intracellular defense against microorganisms while arginase is activated
by Th2 related cytokines such as IL-4, IL-5, and IL-13 which are
responsible for allergic reactions (7, 8). In contrast, the role of
regulatory T cells (Treg) is to suppress over-activated effector T cells
and play a key role in the regulation of Th1/Th2 immune responses
(9–11). Treg secrets regulatory cytokines such as transforming growth
factor (TGF)-β and IL-10 (12).
Over the years, many studies have tried to supply arginine with or
without other nutrition compounds as a therapeutic strategy to restore
the decreased arginine levels in septic and critical ill patients but
the results were inconsistent (13). Recent studies examining L-arginine
monotherapy in experimental sepsis/endotoxemia of porcine model has
shown beneficial effects on the plasma arginine levels without side
effects (14). L-arginine supplementation can also enhance immune
response, increase protein turnover rate, and elevate NO synthesis (15,
16). However, one study showed a higher mortality rate in severe septic
patients with arginine supplementation in the enteral diet (17). With
these inconsistent findings, the previous views of L-arginine supplement
need to be revisited.
Most of the current studies focus on the effect of L-arginine
supplementation for critical ill population in adults. However, study on
the neonatal population remains scarce. In our previous study, we had
found neonate has lower plasma L-arginine level but more abundant
arginase I in polymorphonuclear cells than adult. Exogenous L-arginine
could enhance neonate lymphocyte proliferation through an IL-2
independent manner (18). For newborn, whose more susceptible to arginine
deficiency than adult, more study about the modulatory effects of
L-arginine supplementation are needed.
Supplementation of citrulline as a source of arginine is alternative
therapeutic intervention being studied currently. L-citrulline
supplementation seems to be more effective than L-arginine
supplementation directly for improving arginine level in sepsis. This is
supported by studies showing that treatment with L-citrulline in
endotoxemic rats resulted in higher plasma arginine concentration than
treatment with L-arginine in certain conditions (19, 20). Research on
citrulline supplementation for modulation of neonatal immunity is
limited.
Arginine availability is essential for a normal immune response,
specifically T-cell proliferation and function (21). When arginine is
depleted, the result could lead to increased susceptibility to infection
(22). Neonatal plasma L-Arginine level was previous shown to be lower
than in adults and this can partly explain why newborns more prone to
infection (18). Therefore, the importance of arginine and/or citrulline
to neonatal immunity cannot be underestimated. More study is needed to
explore the influence of exogenous amino acids on neonatal immunity. The
aim of this study is to investigate the immune modulatory effects of
L-arginine and L-citrulline on infant using a rat model. We found
L-arginine and L-citrulline supplementation have different programming
effect on regulatory T-cells function of infant rats
