it has been documented that pregnancy is a unique immunological state with both immune response and tolerance against fetus antigens ( 1 ) .
previous studies demonstrated that the imbalanced immune responses against fetus antigens can result in abnormality in pregnancy .
cytokines as important immune molecules , play crucial roles in regulation of immune responses against microbes and foreign antigens including graft and fetus antigens ( 2 ) .
interleukin-10 ( il-10 ) , as a main anti - inflammatory cytokine , significantly participates in regulation of immune responses against self and foreign antigens in the case of tolerance to these antigens ( 3 - 5 ) .
therefore , alteration in expression of this cytokine during pregnancy may lead to several pathologic conditions such as preterm labor ( ptl ) ( 6 , 7 ) .
ptl is the common disorder in the pregnancy and is defined as birth before the 37 week of gestation ( 8) .
previous studies revealed that ptl can be associated with inflammation : hence , regarding the important roles played by il-10 in the suppression of inflammation , it appears that this cytokine can play key roles in the pathogenesis of ptl .
therefore , the main aim of this review article is to present the status and function of il-10 in the pathogenesis of ptl .
ptl is a birth that occurs before the 37 week of gestation and as described in the previous section the complication is a common disorder in the pregnancy occurring in approximately 10% of deliveries ( 9 ) . in the normal human fetus ,
several organ systems mature between 34 and 37 weeks , and the fetus reaches adequate maturity by the end of this period ( 9 , 10 ) .
the preterm birth is associated with several complications leading to mortality and morbidity such as neurological , respiratory , gastrointestinal and metabolic problems , hematologic disorders , and infection ( 10 ) .
based on the fact that the etiology and the main responsible mechanisms that lead to preterm birth are unknown , several hypotheses are in process worldwide .
il-10 is categorized as an anti - inflammatory cytokine and is produced by several cells including activated macrophages , t regulatory and th2 lymphocytes and so on ( 11 ) .
the main function of this cytokine is to suppress th1 , th2 and b lymphocytes , nk cells , macrophages , and dendritic cells inflammatory functions ( 12 , 13 ) .
1q31 - 1q32 is the location of the il-10 gene ( approximately 5.2 kb ) , which consists of five exons ( 14 ) , and encodes a protein of 178 amino acids called pro - il-10 ( 13 ) .
pro - il-10 activation is done by cleavage of a signal peptide of 18 amino acids ( 13 ) .
it has been demonstrated that il-10r consists of  and  chains and is categorized as a type ii cytokine receptor ( 15 ) . several intracellular signaling pathways will be activated following il-10/il-10r  and  chain interaction by phosphorylation of jak1 ( janus kinase-1 ) and tyk2 ( tyrosine kinase-2 ) , respectively , as intracellular protein kinases ( 16 ) . in a positive feedback , activated jak1 and tyk2 phosphorylate y446 and y496 positions of il-10r  chain ( 17 ) .
the phosphorylation is a place for binding and phosphorylation of signal transducer and activator of transcription 3 ( stat3 ) tyrosine residues ( 18 ) .
homodimerized stat3 is translocated into the nucleus and recognizes stat - binding element ( sbe ) regions at the promoters of several genes including il-10 , anti - apoptotic , cell - cycle - progression , suppressor of cytokine signaling 3 ( socs3 ) genes , and so on ( 19 ) .
several other pathways such as phosphoinositide-3 kinase ( pi3k ) ( 20 ) and mitogen - activated protein kinase ( p38/mapk ) ( 21 ) are also regulated by il-10/il-10r interaction .
based on the aforementioned information , it appears that il-10 may significantly participate in the outcome of pregnancy .
for instance , it is documented that il-10 suppresses the production and function of pro - inflammatory cytokines including il-12 , ifn- , il-1 , and so on ( 22 ) , and numerous studies have reported its expression at the maternal - fetal interface ( 23 - 25 ) .
it was also demonstrated that , under effects of progesterone , il-10 serum levels are elevated , which results in suppression and activation of th1 and th2-type cytokines , respectively ( i.e. , il-10 and il-4 ) .
robertson et al also showed that il-10 mrna and protein is up - regulated in gestational tissues in normal pregnancy .
interestingly , they have concluded that up - regulation of il-10 can be considered as a critical factor for resistance to preterm labor ( 26 ) .
it has been demonstrated that lps could induce preterm labor in some cases ( 27 ) .
experimental studies have shown that exogenous il-10 inhibits lps - induced preterm labor ( 28 , 29 ) . a study by gotsch et al revealed that in 4157 days ( third phase ) after gestation , the concentration of il-10 was increased by high levels of 17-estradiol ( 30 ) .
up - regulation of il-10 and 17-estradiol leads to the suppression of dendritic cells ( dcs ) and consequently inhibits the stimulation of t lymphocytes by dcs ( 30 ) , which is associated with a normal pregnancy .
additionally , another study demonstrated that decreased number of peripheral blood mononuclear leukocytes that produce il-10 , leads to recurrent preterm births during the second trimester ( 31 ) .
it has also been documented that preterm delivery during mid - trimester is associated with unchanged levels of il-10 in amniotic fluid , where the concentration of il-10 needs to be increased ( 32 ) .
our previous study also revealed that serum levels of il-10 were not differed in preterm in comparison to term neonates ( 33 ) .
the results have been confirmed by gotsch et al who reported that il-10 is expressed in high concentrations in the amniotic fluid of normal term women ( 30 ) .
the investigators also showed that spontaneous parturition in either term or preterm gestation is associated with elevated concentrations of il-10 in amniotic fluid ( 30 ) .
increased amniotic fluid concentrations of il-10 during intra - amniotic infection / inflammation have also been reported by gotsch and colleagues ( 30 ) . moreover , another research demonstrated that preterm neonates compared to term neonates , produce higher and lower inflammatory and anti - inflammatory cytokines in response to specific bacteria , respectively ( 34 ) .
therefore , it may result in uncontrolled inflammatory response , which is associated with preterm labor ( 34 ) .
researchers have evaluated the expression profiles of il-10 and cyclo - oxygenase-2 ( cox-2 ) , as an enzyme for producing prostanoids ( prostaglandins , prostacyclin , and thromboxane ) , which are the potential inducers of delivery ( 35 ) .
they have reported that il-10 significantly regulates the expression of cox-2 and consequently prostaglandins , hence , the authors concluded that il-10 plays important roles in countering inflammation that is produced in preterm labor ( 35 ) .
although , the aforementioned studies have demonstrated that the il-10 levels were lower in preterm vs. term delivery , some investigations reported that il-10 levels were high in preterm delivery associated with infection .
for example , it was shown that the cord blood levels of il-10 were significantly increased in infected versus non - infected mothers ( 36 ) .
another study demonstrated that the cord blood il-10 levels are increased during intrauterine infection ( 37 ) .
based on these results , it may be concluded that up - regulation of il-10 in the infected preterm delivery is a normal response of the immune system to regulate the infection - dependent inflammation .
for example , it has been demonstrated that il-10 levels are positively associated with elevated odds ratio of placental - mediated preterm birth ( 38 ) .
it may be related to the infections that have not been examined in the evaluated preterm neonates . according to the data presented here
, it appears that il-10 plays significant roles in the induction of an appropriate pregnancy because its expression is up - regulated in the normal pregnancy , while its production is disrupted during preterm labor .
for example , it has been established that surfactant protein a ( sp - a ) is produced in the fetus to provide signals for the onset of parturition ( 39 ) .
interestingly , the study revealed that sp - a suppresses preterm delivery via tlr2-dependent il-10 production ( 39 ) .
indoleamine 2,3-dioxygenase ( ido ) is an enzyme for catabolism of tryptophan , which is crucial for t lymphocyte activation and proliferation ( 40 ) .
ido regulate maternal immune responses against fetus alloantigens via suppression of maternal t lymphocytes and also up - regulation of anti - inflammatory cytokines such as il-10 ( 40 ) .
additionally , it has been evidenced that tolerogenic dcs plays key roles in the induction of maternal immune tolerance to fetus alloantigens ( 41 ) .
interestingly , il-10 is a potential factor that stimulates the production of tolerogenic dcs ( 42 ) , hence , it can induce a successful pregnancy .
previous investigations identified that regulatory t lymphocytes also significantly participate in induction of maternal immune tolerance to fetus alloantigens and subsequently a successful pregnancy ( 43 ) .
il-10 is not only produced by regulatory t lymphocytes , but also leads to the development of these cells ( 43 ) .
il-10 binding to its corresponded receptor ( il-10r ) leads to activation of the il-10/jak1/stat3 cascade and subsequently phosphorylation of stat3 .
the phosphorylation leads to the production of stat3 homodimer ( stat3/stat3 ) and its translocation to the nucleus can trigger the expression of the target gene ( see the previous section ) , which participates in the induction of a successful pregnancy ( 4446 ) .
as mentioned in the figure , sp - a , 17-esteradiol , ido vitamin d3 , and il-10 genetic variations can alter expression of il-10 .
il-10 inhibits preterm delivery using several mechanisms including development of t regulatory lymphocytes and tolerogenic dcs , activation of the jak1/stat3 pathway , down - regulation of cox-2 , and also inhibition of lps - induced preterm delivery interestingly , genetic research revealed that the genetic variations in the il-10 gene are also associated with preterm delivery .
it has also been evidenced that the polymorphisms within il-10 gene are associated with its expression during pregnancy ( 47 , 48 ) .
for instance , it was shown that il-10 ( rs1800896 ) polymorphism is associated with gram - negative infections in preterm labor ( 49 ) .
the relation between the polymorphisms within the promoter region of il-10 and cervical insufficiency have been reported by warren and colleagues ( 50 ) .
another study also revealed that il-10 ( -1082a ) polymorphism is significantly associated with genitourinary infections and/or inflammation ( 51 ) .
another study has shown that il10 ( -1082)*g plays crucial roles in less than 29 weeks extreme preterm delivery ( 52 ) .
a study on australian population revealed that il-10 82a/-819t/-592a haplotype is associated with preterm delivery ( 53 ) .
interestingly the study demonstrated that this haplotype is more prevalent in women with preterm premature rupture of membranes ( 53 ) .
contrastly , one study was unable to find a relation between il-10 polymorphisms and preterm delivery ( 54 ) .
another study was also unable to find an association between the polymorphisms within il-10 gene ( il10 -1082 g > a , il10 -819 c > t , and il10 -592 c > a ) and spontaneous preterm delivery ( 55 ) .
a study on austrian population demonstrated that il-10 -1082 g / a single nucleotide polymorphism was not associated with preterm delivery ( 56 ) .
no association between this polymorphism and preterm delivery was also demonstrated by brazilian researchers ( 57 ) .
it appears that further studies are essential to complete our knowledge regarding the roles of genetic variations in the induction of preterm delivery .
ptl is a birth that occurs before the 37 week of gestation and as described in the previous section the complication is a common disorder in the pregnancy occurring in approximately 10% of deliveries ( 9 ) . in the normal human fetus ,
several organ systems mature between 34 and 37 weeks , and the fetus reaches adequate maturity by the end of this period ( 9 , 10 ) .
the preterm birth is associated with several complications leading to mortality and morbidity such as neurological , respiratory , gastrointestinal and metabolic problems , hematologic disorders , and infection ( 10 ) .
based on the fact that the etiology and the main responsible mechanisms that lead to preterm birth are unknown , several hypotheses are in process worldwide .
il-10 is categorized as an anti - inflammatory cytokine and is produced by several cells including activated macrophages , t regulatory and th2 lymphocytes and so on ( 11 ) .
the main function of this cytokine is to suppress th1 , th2 and b lymphocytes , nk cells , macrophages , and dendritic cells inflammatory functions ( 12 , 13 ) .
1q31 - 1q32 is the location of the il-10 gene ( approximately 5.2 kb ) , which consists of five exons ( 14 ) , and encodes a protein of 178 amino acids called pro - il-10 ( 13 ) .
pro - il-10 activation is done by cleavage of a signal peptide of 18 amino acids ( 13 ) .
it has been demonstrated that il-10r consists of  and  chains and is categorized as a type ii cytokine receptor ( 15 ) . several intracellular signaling pathways will be activated following il-10/il-10r  and  chain interaction by phosphorylation of jak1 ( janus kinase-1 ) and tyk2 ( tyrosine kinase-2 ) , respectively , as intracellular protein kinases ( 16 ) . in a positive feedback , activated jak1 and tyk2 phosphorylate y446 and y496 positions of il-10r  chain ( 17 ) .
the phosphorylation is a place for binding and phosphorylation of signal transducer and activator of transcription 3 ( stat3 ) tyrosine residues ( 18 ) .
homodimerized stat3 is translocated into the nucleus and recognizes stat - binding element ( sbe ) regions at the promoters of several genes including il-10 , anti - apoptotic , cell - cycle - progression , suppressor of cytokine signaling 3 ( socs3 ) genes , and so on ( 19 ) .
several other pathways such as phosphoinositide-3 kinase ( pi3k ) ( 20 ) and mitogen - activated protein kinase ( p38/mapk ) ( 21 ) are also regulated by il-10/il-10r interaction .
based on the aforementioned information , it appears that il-10 may significantly participate in the outcome of pregnancy .
for instance , it is documented that il-10 suppresses the production and function of pro - inflammatory cytokines including il-12 , ifn- , il-1 , and so on ( 22 ) , and numerous studies have reported its expression at the maternal - fetal interface ( 23 - 25 ) .
it was also demonstrated that , under effects of progesterone , il-10 serum levels are elevated , which results in suppression and activation of th1 and th2-type cytokines , respectively ( i.e. , il-10 and il-4 ) .
robertson et al also showed that il-10 mrna and protein is up - regulated in gestational tissues in normal pregnancy .
interestingly , they have concluded that up - regulation of il-10 can be considered as a critical factor for resistance to preterm labor ( 26 ) .
it has been demonstrated that lps could induce preterm labor in some cases ( 27 ) .
experimental studies have shown that exogenous il-10 inhibits lps - induced preterm labor ( 28 , 29 ) . a study by gotsch et al revealed that in 4157 days ( third phase ) after gestation , the concentration of il-10 was increased by high levels of 17-estradiol ( 30 ) .
up - regulation of il-10 and 17-estradiol leads to the suppression of dendritic cells ( dcs ) and consequently inhibits the stimulation of t lymphocytes by dcs ( 30 ) , which is associated with a normal pregnancy .
additionally , another study demonstrated that decreased number of peripheral blood mononuclear leukocytes that produce il-10 , leads to recurrent preterm births during the second trimester ( 31 ) .
it has also been documented that preterm delivery during mid - trimester is associated with unchanged levels of il-10 in amniotic fluid , where the concentration of il-10 needs to be increased ( 32 ) .
our previous study also revealed that serum levels of il-10 were not differed in preterm in comparison to term neonates ( 33 ) .
the results have been confirmed by gotsch et al who reported that il-10 is expressed in high concentrations in the amniotic fluid of normal term women ( 30 ) .
the investigators also showed that spontaneous parturition in either term or preterm gestation is associated with elevated concentrations of il-10 in amniotic fluid ( 30 ) .
increased amniotic fluid concentrations of il-10 during intra - amniotic infection / inflammation have also been reported by gotsch and colleagues ( 30 ) . moreover , another research demonstrated that preterm neonates compared to term neonates , produce higher and lower inflammatory and anti - inflammatory cytokines in response to specific bacteria , respectively ( 34 ) .
therefore , it may result in uncontrolled inflammatory response , which is associated with preterm labor ( 34 ) .
researchers have evaluated the expression profiles of il-10 and cyclo - oxygenase-2 ( cox-2 ) , as an enzyme for producing prostanoids ( prostaglandins , prostacyclin , and thromboxane ) , which are the potential inducers of delivery ( 35 ) .
they have reported that il-10 significantly regulates the expression of cox-2 and consequently prostaglandins , hence , the authors concluded that il-10 plays important roles in countering inflammation that is produced in preterm labor ( 35 ) .
although , the aforementioned studies have demonstrated that the il-10 levels were lower in preterm vs. term delivery , some investigations reported that il-10 levels were high in preterm delivery associated with infection .
for example , it was shown that the cord blood levels of il-10 were significantly increased in infected versus non - infected mothers ( 36 ) .
another study demonstrated that the cord blood il-10 levels are increased during intrauterine infection ( 37 ) .
based on these results , it may be concluded that up - regulation of il-10 in the infected preterm delivery is a normal response of the immune system to regulate the infection - dependent inflammation .
for example , it has been demonstrated that il-10 levels are positively associated with elevated odds ratio of placental - mediated preterm birth ( 38 ) .
it may be related to the infections that have not been examined in the evaluated preterm neonates . according to the data presented here
, it appears that il-10 plays significant roles in the induction of an appropriate pregnancy because its expression is up - regulated in the normal pregnancy , while its production is disrupted during preterm labor .
for example , it has been established that surfactant protein a ( sp - a ) is produced in the fetus to provide signals for the onset of parturition ( 39 ) .
interestingly , the study revealed that sp - a suppresses preterm delivery via tlr2-dependent il-10 production ( 39 ) .
indoleamine 2,3-dioxygenase ( ido ) is an enzyme for catabolism of tryptophan , which is crucial for t lymphocyte activation and proliferation ( 40 ) .
ido regulate maternal immune responses against fetus alloantigens via suppression of maternal t lymphocytes and also up - regulation of anti - inflammatory cytokines such as il-10 ( 40 ) .
additionally , it has been evidenced that tolerogenic dcs plays key roles in the induction of maternal immune tolerance to fetus alloantigens ( 41 ) .
interestingly , il-10 is a potential factor that stimulates the production of tolerogenic dcs ( 42 ) , hence , it can induce a successful pregnancy .
previous investigations identified that regulatory t lymphocytes also significantly participate in induction of maternal immune tolerance to fetus alloantigens and subsequently a successful pregnancy ( 43 ) .
il-10 is not only produced by regulatory t lymphocytes , but also leads to the development of these cells ( 43 ) .
il-10 binding to its corresponded receptor ( il-10r ) leads to activation of the il-10/jak1/stat3 cascade and subsequently phosphorylation of stat3 .
the phosphorylation leads to the production of stat3 homodimer ( stat3/stat3 ) and its translocation to the nucleus can trigger the expression of the target gene ( see the previous section ) , which participates in the induction of a successful pregnancy ( 4446 ) .
as mentioned in the figure , sp - a , 17-esteradiol , ido vitamin d3 , and il-10 genetic variations can alter expression of il-10 .
il-10 inhibits preterm delivery using several mechanisms including development of t regulatory lymphocytes and tolerogenic dcs , activation of the jak1/stat3 pathway , down - regulation of cox-2 , and also inhibition of lps - induced preterm delivery interestingly , genetic research revealed that the genetic variations in the il-10 gene are also associated with preterm delivery .
it has also been evidenced that the polymorphisms within il-10 gene are associated with its expression during pregnancy ( 47 , 48 ) .
for instance , it was shown that il-10 ( rs1800896 ) polymorphism is associated with gram - negative infections in preterm labor ( 49 ) .
the relation between the polymorphisms within the promoter region of il-10 and cervical insufficiency have been reported by warren and colleagues ( 50 ) .
another study also revealed that il-10 ( -1082a ) polymorphism is significantly associated with genitourinary infections and/or inflammation ( 51 ) .
another study has shown that il10 ( -1082)*g plays crucial roles in less than 29 weeks extreme preterm delivery ( 52 ) .
a study on australian population revealed that il-10 82a/-819t/-592a haplotype is associated with preterm delivery ( 53 ) .
interestingly the study demonstrated that this haplotype is more prevalent in women with preterm premature rupture of membranes ( 53 ) .
contrastly , one study was unable to find a relation between il-10 polymorphisms and preterm delivery ( 54 ) .
another study was also unable to find an association between the polymorphisms within il-10 gene ( il10 -1082 g > a , il10 -819 c > t , and il10 -592 c > a ) and spontaneous preterm delivery ( 55 ) .
a study on austrian population demonstrated that il-10 -1082 g / a single nucleotide polymorphism was not associated with preterm delivery ( 56 ) .
no association between this polymorphism and preterm delivery was also demonstrated by brazilian researchers ( 57 ) .
it appears that further studies are essential to complete our knowledge regarding the roles of genetic variations in the induction of preterm delivery .
due to the aforementioned results , it appears that il-10 plays key roles in the induction of a normal delivery via development of tolerogenic dcs , t regulatory lymphocytes , and up - regulation of stat3 target genes .
up - regulation of this anti - inflammatory cytokine leads to suppression of nk cells and t lymphocytes against their fetus alloantigens .
the factors that alter the expression of il-10 , including infections and genetic variations within il-10 gene , could determine the outcome of pregnancy .
additionally , it has also been demonstrated that preterm delivery is associated with several short and long - term health problems .
it may be hypothesized that alteration in expression of il-10 is also associated with the incidence of the complications .
moreover , il-10 can decline the pathologic effects of inflammation that is prevalent in the preterm delivery .
therefore , it appears that regulation of il-10 expression during normal pregnancy is cautiously regulated .
 imbalanced immune responses against fetus alloantigens can lead to abnormality in pregnancy . interleukin-10 
 ( il-10 ) plays key roles in regulation of immune responses against self and foreign antigens to induce tolerance to these antigens . 
 therefore , alteration in expression of il-10 during pregnancy may result in several pathologic conditions such as preterm labor . 
 il-10 leads to a normal pregnancy via several molecular mechanisms including development of tolerogenic dendritic cells , t regulatory lymphocytes and activation of the jak1/stat3 pathway in the target cells . 
 this review has collected recent data regarding the status of il-10 expression during term and preterm deliveries and also its molecular mechanisms that lead to a normal pregnancy . 
Introduction
Preterm labor
IL-10, structure and intracellular signaling
IL-10 and delivery
Conclusion