The Role of Cytokines in

Uteroplacental Dysfunction
By: Melda Nur Rahmani

INTRODUCTION
Pre-eclampsia is a multisystem disorder of

unknown etiology that is unique to human

pregnancy.
It is characterized by abnormal vascular
response to placentation that is associated
with increased systemic vascular resistance,
enhanced platelet aggregation, activation of
the coagulation system, and endothelial-cell
dysfunction.

Research addressing this disorder has been

extensive during the past decade, but has not

resulted in substantial improvement.
Recent attention has focused on elucidating
the immuno-biological roles of cytokines in
normal human pregnancy following the
accumulated reports of complex cytokine
activity within uteroplacental tissues.

Epidemiology
Pre-eclampsia affects approximately 28% of

all pregnancies worldwide

Preeclampsia is one of the leading causes of
maternal and perinatal morbidity and
mortality

Preeclampsia is much more common in women

who are pregnant for the first time.Women who

have previously been diagnosed with
preeclampsia are also more likely to experience
preeclampsia in subsequent pregnancies.
Preeclampsia is also more common in women
who have preexistinghypertension,obesity,
diabetes,autoimmunediseases such asSLE,
various inherited thrombophilias such as,
renal disease, multiple gestation (twinsor
multiple birth), and advanced maternal age.

There is no definitive known cause of

preeclampsia, though it is likely related to a
number of factors. Some of these factors
include:
Abnormalplacentation
Immunologic factors
Prior or existing maternal pathology
Dietary factors
Environmental factors, e.g. air pollution

What is Cytokines?
Cytokine is a small protein released by cells

that has a specific effect on the interactions

between cells, on communications between
cells or on the behavior of cells.
The cytokines includes the interleukins,
lymphokines and cell signal molecules, such
astumor necrosis factor and the interferons,
which trigger inflammation and respond to
infections.

Inflammatory cytokines
Proinflammatory cytokines

Itis a cytokine which promotes systemic

inflammation. Examples include IL-1 and TNF
alpha. When they are administered to humans,
they produce fever, inflammation, tissue
destruction, and, in some cases, shock and death.
Anti-inflammatory cytokines
It is a series of immunoregulatory molecules that
control the proinflammatory cytokine response.
Major anti-inflammatory cytokines include
interleukin (IL)-1 receptor antagonist,IL-4,IL-6,
IL-10,IL-11, andIL-13. Specific cytokine receptors
for IL-1, tumor necrosis factor-alpha, and IL-18
also function as proinflammatory cytokine

The role of cytokines in the

pathogenesis of
preeclampsia
The cause of endothelial damage in preeclampsia is

unknown, but the activation of neutrophils may

occur at the same vascular damage in the nonpregnant women.
It is reported that the concentration of neutrophil
elastase, a specific marker for neutrophil activation
in vivo, increased in the peripheral circulation of
preeclampsia. Cytokines can stimulate the
activation of neutrophils, the expression of von
Willebrand factor, and cell adhesion to the
endothelium resulting vascular damage.

Preeclampsia is started by the inadequate

cytotrophoblast invasion. It causes the repair

(remodeling) of the ineffective vascular from the
uterine spiral arteries and lead to insufficient placental
perfusion, as well as the deployment of vascular
endothelial dysfunction of the mother. The release of
circulation factors such (VEGF) receptor,
autoantibodies against angiotensin II type I receptor
and inflammatory cytokines including TNF- and IL-6
may provide an important mediator for both activation
and endothelial dysfunction.
Oxidative imbalance in preeclampsia is likely to be
related to the activity of cytokines, particularly TNF-.
Bioactive TNF- levels increased in preeclampsia.
Antioxidants are selectively inhibit the release of TNF as it can control the oxidation-reduction status of
glutathione, which is very important as an endogenous
modulator of TNF- production.

Immune activation and cytokine

production in preeclampsia
Preeclampsia has long been thought to be a disease

based on immunology. In preeclampsia, the shallow

cytotrophoblast invasion and incomplete
endovascular invasion inhibit the important
morphological changes of vascularization of the
uterine blood vessels.
As a result, the average diameter of a third arterial
blood vessels less than half the myometrium
arteries isolated from the placenta of normal
pregnancy. This can allow interactions between
activated immune cells and the appearance of
proinflammatory cytokines to increase the degree of
characteristic of chronic inflammatory conditions.

The role of cytokines in

mediating blood pressure
response to ischemia
It has been reported the levels of TNF- and IL-6

serum increased in mice, with decreased uterine

perfusion pressure and the release of TNF- or IL6 chronically in mice pregnant increases arterial
pressure and a decrease in renal plasma flow and
glomerular filtration rate. These findings show
that TNF- and IL-6 may play an important role in
mediating hypertension and decreased renal
hemodynamics which are observed during uterine
perfusion pressure in pregnant rats.

Interactions between endothelial

and inflammatory cytokines
Endothelial damage is the stimulus formation of

endothelin (ET-1), increased production of ET-1 and ETA

receptor activation may also play a role in the
pathophysiology of hypertension during pregnancy. ET1 concentrations in the plasma was measured in
several studies involving normal and preeclamptic
pregnant women. Most researchers found
concentrations of ET-1 plasma is about 2-3 times higher
in women with preeclampsia.
The increase of ET-1 in plasma which takes long is
comparable to those measured in women with
preeclampsia may play a role in mediating the decline
of renal function and the increase of arterial pressure
which were observed in women with preeclampsia.

The interaction between the

system and the reninangiostensin cytokines
Angiostensin II effect in raising blood

pressure caused by the effects of changes

in kidney function, increased peripheral
resistance of blood vessels, and increased
activity of the sympathetic nervous
system. Now the evidences have been
found to suggest that there is a
proinflammatory mechanism of
angiostensin II in causing hypertension.
Angiostensin II does not only increases the
synthesis of TNF-a and IL-6 immune cells,

DISCUSSION
Research by Orshal and Khalil showed novelties in

the mechanisms of cytokines affect vascular

function in cardiovascular disease associated with
an increase in proinflammatory cytokines such as
IL-6 and TNF- They found that IL-6 induces a
greater inhibition of the vascular relaxation and
increase contraction of the systemic blood vessel
in pregnant rats, it supports the opinion of IL-6 as
potential mediators to increase vascular
resistance associated with hypertension during
pregnancy.

Some research suggests an important role of TNF-

in preeclampsia. Where the serum levels of TNF was higher in preeclampsia compared to normal
pregnancy, serum levels of TNF- increased
significantly in preeclampsia 14.15 pg / ml
compared with normal pregnancies 5.71 pg / ml,
(p <0.001) This study aimed to evaluate the
proinflammatory cytokine TNF in patients with
preeclampsia

Other studies, in normal pregnant

obtained serum levels of TNF- is 0.56

9.3 pg / ml, whereas in preeclampsia 67.66
61.83 pg / ml. (P <0.001). there were no
differences in serum levels of TNF- on
maternal age, and mean arterial pressure
either in normal pregnancies or
pregnancies with preeclampsia.

Summary
Cytokines have been demonstrated as one of the

important causative factors for endothelium activation in

pre-eclampsia.
Inflammatory cytokines are known to regulate the gene
expression of signaling molecules involved in endothelial
activation. IL-1b has been shown to induce expression of
cell adhesion molecules in endothelial cells, which in turn
may contribute to the loss of endothelial function through
increased neutrophil adhesion.
TNFa, which has emerged as an important factor involved
in the pathogenesis of preeclampsia has been shown to be
involved in transcriptional regulation of PDGF and ET-1
genes.

Thus, cytokines-induced changes in

endothelial cell markers suggest a link

between cytokine dysregulation and
endothelial dysfunction in pre-eclampsia.
Therefore, cytokine network in human
pregnancy plays a role not only in immune
protection of the fetal-allograft, but also in
regulating other complex events of pregnancy
including implantation, trophoblast cell
invasion and placental growth and
development.