Several studies point the role of cytokines in the maintenance
of pregnancy and the formation of placenta and deciduan87.
Disturbance of normal cytokine expression profile or imbalance between them
could lead to pregnancy complications 4az n87. NK cells produces different type of cytokines and based on classified
to 4 groups. NK1 cells that produce type 1 cytokines similar to Th1 (IFN-g,
TNF-a), Nk2 cells that produce type 2 cytokines (IL-4, IL-5) and immunoregulatory NK cells including NK3 (TGF-b) and
NKr1 (IL-10). It has been shown that cytokine profile of NK cells in women
suffering from RSA is different from healthy pregnant womenn2. Studies in
murine model also has shown that Th2 cytokine profile is associated with a
successful pregnancy while Th1 cytokines lead to pregnancy
complications  n50. MSCs have the capacity to modulate
several effector function of immune cells that make them an ideal candidate to
treatment immune related disorderref peda shavad. There are some studies that
investigate the effect of MSCs on NK cells. These studies have shown that MSCs
could inhibit proliferation, cytotoxicity of NK cells and also alter their
cytokine profilen79, n62., Our
Previous studies indicated that adipose–derived MSCs could reduced abortion
rate in abortion prone micemaghale sedighi, to investigate the mechanisms
that are involved in these observations  . In the present study, we investigated
cytokine profile of uNK cells after MSCs therapy. We observed that the
administration of MSCs could significantly reduced pro- inflammatory cytokines
and increased anti- inflammatory cytokines in abortion- prone matings. These
result indicated that MSCs therapy successfully induced NK2 and NKr1 at the
feto- maternal interface and thereby improved outcome of pregnancy.

There are a lot evidence indicates that During mid
gestation th2 cytokines by modulation the pro- inflammatory and cytotoxic
response are essential for successful pregnancy while Th1 cytokines are
associated with lack of fetal tolerance at mid gestation. n90,n87. Tangri et
al. reported that placenta of CBA/J x DBA/2 cross mice Produces more amount of
Th1 cytokines (IFN-g, TNF-a and IL-2) compared with CBA/J x BALB/C cross
mice.44 az n50. Their studies also showed that stimulated
peripheral blood lymphocytes of abortion-prone
mice produced higher amount of Th1 cytokines than in normal pregnancy 45 az
n50. Our data also showed that NK1 increased and NK2, NKr1 decreased at the
feto-maternal interface in abortion- prone mice compared with normal pregnancy.
In the present study , thus it was important to demonstrate whether MSCs
therapy could changes in cytokine profile of uNK cells at the feto-maternal
interface. To test this hypothesis and further
illuminate the mechanisms involved in MSCs therapy that reduced abortion rate,
we analyzed the expression of pro- and anti- inflammatory cytokines in uNK
cells at the feto- maternal interface. We showed that MSCs therapy could
reduced NK1 and increased NK2 and Nkr1 at the feto- maternal interface. The
result of the present study demonstrated that MSCs may upregulate the
expression of IL-4 and IL-10 in uNK cells and downregulate IFN-g production and
thereby maintain tolerance at the feto- maternal interface. IL-4 is a pleiotropic
anti-inflammatory cytokine which mainly acts through the suppression of the pro- inflammatory
responses. Different immune cells produce IL-4, including activated T cells, mast
cells, basophils, eosinophils, regulatory B cells, NKT cell and NK cells.  Several studies
indicate a role for IL-4 in the development of Treg Which
is essential for successful pregnancyn90. IL-10 is also an anti- inflammatory
cytokine. Main producer of IL-10 at the feto- maternal interface are uNK cells,
and Tregs36 az n90. IL-10 exerts its anti-inflammatory effect
through inhibition of pro- inflammatory
cytokines34 az n90.IL-10 also suppress Th1 cells by effect on the antigen
presenting cells to induce anergy or Treg cells.n87.Our previous study showed
that MSCs therapy increased the level of Treg in abortion prone- micemaghale
salek, these data illuminated a mechanisms for the effect of MSCs therapy in
this model.  MSCs probably by
upregulating IL-4 and IL-10, increased the level of Treg Which leads to the maintenance of
tolergenic microenvironment .

In conclusion, the present study reports that MSCs could reduce abortion
rate by upregulate the expression of IL-4
and IL-10 in uNK cells and downregulate IFN-g production. These data suggest
that MSCs shift cytokines from Th1 predominance to th2 bias and thereby maintain tolergenic
microenvironment at the feto- maternal interface.


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