Chemokines Modulate the Activity of Several Cells of the Immune System: Relationship with the Pathogenesis of Endometriosis

  

    
Family
    
Chemokine
    
Original Name
    
Receptors
    
Gene Locus
  
  

    
CXC
    
CXCL1
    
GROα / MIP-2
    
CXCR2
    
24q21
  
  

    
 
    
CXCL2
    
GRO β
    
CXCR2
    
4q21
  
  

    
 
    
CXCL3
    
GRO γ
    
CXCR2
    
4q21
  
  

    
 
    
CXCL4
    
PF-4
    
CXCR3-B
    
4q21
  
  

    
 
    
CXCL5
    
ENA-78
    
CXCR2
    
4q21
  
  

    
 
    
CXCL6
    
GCP-2
    
CXCR2
    
24q21
  
  

    
 
    
CXCL7
    
NAP-2
    
CXCR2
    
4q21
  
  

    
 
    
CXCL8
    
IL-8
    
CXCR2 + CXCR1
    
24q21
  
  

    
 
    
CXCL9
    
MIG
    
CXCR3-A
    
4q21
  
  

    
 
    
CXCL10
    
IP-10
    
CXCR3-A
    
4q21
  
  

    
 
    
CXCL11
    
I-TAC
    
CXCR3-A
    
4q21
  
  

    
 
    
CXCL12
    
SDF-1
    
CXCR4
    
10q11.21
  
  

    
 
    
CXCL13
    
BCA-1
    
CXCR5
    
4q21
  
  

    
 
    
CXCL14
    
BRAK
    
?
    
5q31.1
  
  

    
 
    
CXCL15
    
Lungkine
    
?
    
?
  
  

    
 
    
CXCL16
    
CXCL16
    
CXCR6
    
17p13
  
  

    
CC
    
CCL1
    
I-309
    
CCR8
    
17q11
  
  

    
 
    
CCL2
    
MCP-1
    
CCR2
    
17q12
  
  

    
 
    
CCL3
    
MIP-1α
    
CCR1, CCR5
    
17q12
  
  

    
 
    
CCL4
    
MIP-1β
    
CCR5
    
17q12
  
  

    
 
    
CCL5
    
RANTES
    
CCR5
    
?
  
  

    
 
    
CCL6
    
C10
    
?
    
?
  
  

    
 
    
CCL7
    
MCP-3
    
CCR1,CCR2,CCR3
    
17q11
  
  

    
 
    
CCL8
    
MCP-2
    
CCR3, CCR5
    
17q11
  
  

    
 
    
CCL9
    
MIP-1γ
    
?
    
?
  
  

    
 
    
CCL10
    
CCL10
    
?
    
?
  
  

    
 
    
CCL11
    
Eotaxin
    
CCR3
    
17q11
  
  

    
 
    
CCL12
    
MCP-5
    
CCR2
    
?
  
  

    
 
    
CCL13
    
MCP-4
    
CCR2, CCR3
    
17q11
  
  

    
 
    
CCL14
    
HCC-1
    
CCR1, CCR5
    
17q12
  
  

    
 
    
CCL15
    
HCC-2/MIP-1δ/ Leotactin-1
    
CCR1, CCR3
    
17q12
  
  

    
 
    
CCL16
    
HCC-4/LEC
    
CCR1, CCR2
    
17q12
  
  

    
 
    
CCL17
    
TARC
    
CCR4
    
16q13
  
  

    
 
    
CCL18
    
PARC/DC-CK1
    
?
    
17q12
  
  

    
 
    
CCL19
    
MIP-3β/ELC
    
CCR7
    
9p13.3
  
  

    
 
    
CCL20
    
LARC/MIP-3α
    
CCR6
    
2q36.3
  
  

    
 
    
CCL21
    
SLC/6Ckine
    
CCR7
    
9p13.3
  
  

    
 
    
CCL22
    
MDC
    
CCR4
    
16q13
  
  

    
 
    
CCL23
    
MPIF-1
    
CCR1
    
17q12
  
  

    
 
    
CCL24
    
Eotaxin 2/MPIF-2
    
CCR3, CCR5
    
7q11
  
  

    
 
    
CCL25
    
TECK
    
CCR9
    
19q13.3
  
  

    
 
    
CCL26
    
Eotaxin-3
    
CCR3
    
7q11
  
  

    
 
    
CCL27
    
ESkine/MCC/Ctack
    
CCR10
    
9p13.3
  
  

    
 
    
CCL28
    
MEC
    
CCR3, CCR10
    
5p12
  
  

    
XC
    
XCL1
    
Linfotactina α
    
XCR1
    
1q24
  
  

    
 
    
XCL2
    
Linfotactina β
    
XCR1
    
1q24
  
  

    
CX3C
    
CX3CL1
    
Fractalkine
    
CX3CR1
    
16q13
  

Table 1:  Human Chemokines identified: receptors, ligands (standardized and alternative nomenclature) and gene locus [22].

Besides working as lymphocyte chemotactic agent, studies on chemokines and their receptors revealed other important roles for these molecules, such as their relationship with tumor metastases and, conversely, inhibition of tumor cell growth, as well as in infections and autoimmune diseases like rheumatoid arthritis and multiple sclerosis [23-25].

Chemokines play a paramount role in tumor progression. Chronic inflammatory processes may cause tumors formation, and both tumor and stroma cells produce chemokines and other cytokines. They operate both by autocrine and peregrine mechanisms on sustaining tumor cells growth, inducing angiogenesis, and promoting a decrease in immune surveillance [25].

Chemokines and their receptors also play an important role in the development and maintenance of innate and adaptive immunity [25]. Furthermore, they help in the process of wound healing and angiogenesis. However, if the physiological role of chemokines is subverted or chronically enlarged, the disease is likely to develop. Since chemokines are involved in the pathophysiology of chronic inflammation, tumorigenesis and metastasis, as well as autoimmune diseases, the potential use of chemokine antagonists has been evaluated in targeted therapies [21]. The chemokines role of modulating the activity of other cells of the immune system has not been fully studied and elucidated yet, and their role in the pathogenesis of endometriosis is the target of a growing number of studies.

Inflammatory microenvironment in the peritoneal cavity of patients with endometriosis: chemokines role

Many authors have suggested that the pathogenesis of endometriosis entails inflammatory aspects and activation or inactivation of many cells involved in the process would be affected by chemokines. We will show the first and the last report of the involvement of each chemokine with endometriosis, trying to follow a sequence since the first description.

The first article linking endometriosis and chemokines (Khorram et al., 1993) [26] showed that the peritoneal fluid concentration of CCL5 (RANTES or Regulated upon Activation, Normal T cell Expressed and Secreted) was significantly elevated in women with endometriosis compared with controls and that those levels correlated positively with the disease stage. Zhao et al., in 2002 [27], discovered that endometrial stroma cells have receptors for hydrocarbons and could stimulate the production of RANTES through the use of dioxin. It is known that dioxin and its similes (TCDD/PCBs) affects the endometrial physiology, however, its mechanism is speculative and remains uncertain due to the difficulty in evaluating its exposure in intrauterine life, childhood and adulthood, along with the limitations of its reproduction in vitro [28]. This, in turn, could induce the recruitment of inflammatory cells, corroborating to the development and progression of endometriosis.

In 2010, Wang et al. [29] evaluated the relationship between TECK (thymus-expressed chemokine), dioxin and 17α-estradiol in endometrial stroma cell modulation. They found that the combination of dioxin and 17α-estradiol with endometrial stroma cells increases TECK secretion in endometrial cells and allows their invasion through the rise on the expression of matrix metalloproteinase 2 and 9 (MMP- 2 and MMP-9). Besides that, the use of neutralizing anti-TECK can effectively decrease the potential of invasion of those cells and expression of MMP-2 and MMP-9. Finally, the authors demonstrated that RANTES can induce surface markers of macrophage tolerance in vitro and inhibit the apoptotic effects of macrophage-like cells on endometrial stroma cells.

In 2012, Li et al. [30] evaluated the invasive ability of endometrial stroma cells under the action of the chemokine CCL2 (MCP- 1), applying a dosage by ELISA in patients with and without endometriosis. They found that the secretion of MCP-1 in topical endometrial stroma cells of patients with endometriosis was increased compared with women without the disease. Also, they found that MCP-1 may enhance the viability, proliferation and invasion of stroma cells depending on the duration and amount of exposure to it. Likewise, the use of anti-MCP-1 and/or CCR2 receptor antagonists could completely abolish the stimulatory function of MCP-1. This chemokine was first studied by Akoum et al. [31], who demonstrated that women with endometriosis have increased peritoneal fluid MCP-1 levels and these results correlate with the severity of disease.

More recently, Margari et al., [32] evaluating the peritoneal fluid concentrations of MCP-1 in patients with different stages of endometriosis and comparing with controls, found a decrease in the concentrations of MCP-1 in stage I endometriosis, which is even larger in stage II, in contrast to stage III and IV, which exhibit concentrations similar to the controls.

In women, serum levels of MCP-1 were compared in infertile women with and without endometriosis and Gmyreket et al. [33] found an increased and significant level of this chemokine in patients with endometriosis when compared with a cohort of infertile women.

Another study showed differences in the follicular fluid in patients undergoing IVF (In Vitro Fertilization) with and without endometriosis. Xu et al. [34] found that a RANTES level in the follicular fluid was significantly higher in patients with endometriosis when compared with patients with tubal infertility.

Antinolo et al. in 2004 [35], evaluated the frequency of polymorphisms in RANTES receptor and MCP-1 in women with and without endometriosis and did not find significant differences, although those chemokines are usually increased in peritoneal fluid of patients with endometriosis. This fact led Na et al. in 2011 [36], to evaluate the effects of the peritoneal fluid of patients with endometriosis in chemokines secretion by leukocytes. In short, they evaluated patients with and without endometriosis and compared the effect of adding peritoneal fluid of these patients to a neutrophils, monocytes and T cells culture. They observed that these cells secrete varying levels of MCP-1, RANTES and MIP-1 α in response to stimulation from the peritoneal fluid of patients with endometriosis.

CX3CL1 (Fraktalkine) is one of the most studied chemokines in endometriosis researches [37,38]. Evaluating healthy women in 2006, Watanabe et al. [38] showed that more CX3CL1 is higher expressed in the endometrial at the secretory phase when compared to the proliferative phase, illustrating that such presence could be responsible for the regulation of the immune environment by attracting cells such as NK, which plays a major role in the immune system of vertebrates. These lymphocytes are capable of differentiating between virusinfected cells, neoplastic cells and normal cells.

In 2010, Hirata et al. [39] evaluated the recruitment and migration of T helper 17 (Th17) cells under the influence of the chemokine CCL20. Using flow cytometry in endometrial of patients with endometriosis, they found that Th17 cells express CCR6, the CCL20 receptor. Using immuno histochemistry they found that CCL20 is also expressed in stroma and epithelial cells of endometrial tissue. Moreover, they found that CCL20 provided selective migration of Th17 lymphocytes, and IL-1α, TNFα -and IL-17A increased the secretion of CCL20 in cultures of endometrial stroma cells.

In 2009, Kim et al. [40] had already published a similar study, however evaluating the secretion of CXCL8 and CXCL10 in cultures of neutrophils, CD4+ lymphocytes, and monocytes. The addition of peritoneal fluid in the culture of these cells led to a significant increase in secretion of CXCL8 and CXCL10. In 2009, Galleri et al. [41] found reduced concentrations of CXCL10 in serum and peritoneal fluid of patients with endometriosis when compared to patients without it.

In 2011, Sudqvist et al. [42] evaluated 1149 samples of 798 Caucasian patients with endometriosis and scanned the presence of genetic polymorphism. They unveiled an association between CCL21 rs2812378 and moderate to severe endometriosis, throwing light on the different forms in the pathogenesis of endometriosis for indicating the type and severity of the disease. Comparing with Rheumatoid Arthritis (RA), both diseases seem to be associated with variants of the CCL21 gene but in different alleles (G in RA and A in endometriosis), suggesting a differentiated functional role of the allele.

In a recent study, our group [43] found a relationship between chemokines that regulate the activity of NK (Natural Killer) and T-reg (T regulatory) cells in patients with endometriosis. We compared the expression of the mentioned chemokines in the topic (patients and controls) and ectopic endometrial (patients). Of those associated with NK cells, CX3CL1 and CXCL12 expression was significantly greater in foci of endometriosis compared to the eutopic endometrium in patients and controls. And of the chemokines associated with T-reg cells, CCL17 expression was significantly greater in the eutopic endometrial of patients with recto sigmoid endometriosis compared to the foci of endometriosis or eutopic endometrial of patients with retro cervical endometriosis or to disease-free women. An NK and T-reg cell seems to play a fundamental role in endometriosis. These cells when inactive, underactive or even when functioning normally, appears to play a fundamental role in the genesis and/or maintenance of this disease. Knowing how these chemokines modulate this inflammatory response represents a special key to understanding the genesis and maintenance of this disease.

Reis et al. [44] published a review which shows the relationship between chemokines and the hormone regulation exercised over them. A complementary and possibly mechanism of endometriosis formation derives from an imbalanced regulation of cell fate with reduced susceptibility to apoptosis. Some chemokines, such as RANTES and IL-8, may be involved in the amplification of the local immune response and the survival of endometriosis cells increasing its proliferation or even attenuating the apoptosis. Despite the sex steroids remains the first line targets for medical therapies, the effects of estrogens and progestagens on endometriosis cells are only partially known. Estrogens are not only proliferative, but also Proinflammatory and ant apoptotic in endometrial cells, and these effects are exacerbated in women with endometriosis through the action of some chemokines, kinases and Bcl-2. Progestogens also are effective in inducing apoptosis in endometrial epithelial cells through the inhibition of Bcl-2 and the stimulation of Bax and ERK pathways. This is an interesting point of view and shows some new possibilities for diagnosis and treatment of this disease, in addition to showing the importance of studying this group of inflammatory mediators.

Several chemokines play a critical role in angiogenesis associated with endometriosis. IL-8 (CXCL8) that is produced both in the topic and ectopic endometrial induces the proliferation of stroma cells in them, which may be considered an angiogenic inductor [45,-47]. Besides, Nishida et al. [45] also demonstrated that endometriosis cells induced by TNFα produce ENA-78 and GROα, which are CXC chemokines pervaded by chemo attractive factors, and closely related to neoangiogenesis. Moreover, IL-8 is one of the most studied chemokines correlated to endometriosis. The first article regarding this issue [48] correlated the levels of this chemokine in the peritoneal fluid of women with and without the disease. IL-8 concentration was higher in women with endometriosis than in controls with a positive correlation with the stage of the disease. Several other studies had similar results in the past few years [49-51] and Ohata et al. [52] found a correlation between ovarian endometrial and the serum concentrations of this chemokine. Carmona et al. [53] studied serum concentrations of IL-6 and IL-8 in patients with and without endometriosis. They carried out a case control study comparing patients with ovarian endometrium, deep infiltrating endometriosis and healthy women without endometriosis. They found that the presence of ovarian endometrioma is related to an increase in serum concentrations of IL-6 and IL-8.

In 2012, Malhotra et al. [51], evaluating angiogenic cytokines, performed dosage of IL-8 and leptin in the peritoneal fluid of patients with endometriosis and then compared them with fertile controls. They found that both IL-8 and leptin are increased in peritoneal fluid of patients with peritoneal endometriosis in early or advanced stages, but are decreased in patients with ovarian endometrial. In addition, they found no differences related to infertility or chronic pelvic pain.

Contributing to the discussion on IL-8, Manabe et al. in 2011 [54], evaluated the expression of CXCL16, and its receptor CXCR16 in ovarian endometriomas, using immuno histochemistry and Western blot, and found that both stroma cells and epithelial cells in ovarian endometrial expressed continuously to this chemokine, independent of the menstrual cycle phase. They also discovered that the CXCL16 induced the production of IL-8 in endometriosis stroma cells in vitro.

Recently, eotaxin (CCL11), which belongs to the family of CC chemokines, was reported as a neoangiogenic factor in the development of endometriosis [55,56]. Ouyang et al. [55] reported an increase in expression of IL-4 in the peritoneal fluid of women with endometriosis that resulted in an increase in expression of eotaxin. This chemokine plays an important role in the formation of new blood vessels in endometriosis stroma cells, and can be one of those responsible for the subsequent development of the disease. However, the first report showing the correlation of this chemokine with endometriosis [57] found higher levels of peritoneal fluid concentrations of CCL11 in patients with endometriosis and this increase was even more evident in patients with advanced stages of the disease.

Conclusion

Although the pathogenesis of endometriosis is not completely clear, there are several studies including chemokines as likely players in the development of this disease. Additional research evaluating the role of each chemokine along with clinical trials can contribute to a better understanding of the pathogenesis of endometriosis, as well as be useful in developing a noninvasive diagnosis and feasible therapeutic in the future.

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