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

Review Article

Austin J Reprod Med Infertil.2015; 2(6): 1032.

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

Bellelis P*, Abrao MS, Baracat EC and Podgaec S

Department of Obstetrics and Gynecology, University of Sao Paulo Medical School, Brazil

*Corresponding author: Patrick Bellelis, Department of Obstetrics and Gynecology, University of Sao Paulo Medical School, 05007-002 Sao Paulo, Brazil

Received: May 04, 2015; Accepted: October 20, 2015; Published: October 22, 2015


Endometriosis is a highly prevalent inflammatory condition associated with impaired immune response in the peritoneal cavity and uterus. Evidence points to an involvement of inflammatory mediators such as chemokines in the pathogenesis of this disease. Chemokines are a large family of structurally homologous cytokines that stimulate leukocyte movement and regulate their migration from blood to tissues, also known as chemotactic cytokines. Several chemokines including interleukin-8, Growth-Related Oncogene (GRO) alpha, RANTES, Macrophage Inflammatory Protein (MIP-1) were described as increased in peritoneal fluid of patients with endometriosis. CCL2 and CCL20 were involved in the activation and migration of inflammatory cells in patients with endometriosis. Moreover, the influences of environmental factors such as dioxin in the development of endometriosis appear to be related to the stimulus that RANTES and thymus-expressed chemokine (TECK) could have on them. Furthermore, the peritoneal fluid of patients with endometriosis seem to have an effect on neutrophils, macrophages and T cells making them to secrete more chemokines, such as CXCL10 and CXCL8. The existences of genetic polymorphisms of chemokines were also studied, and an association between rs2812378 and CCL21 was related to advanced stages of endometriosis.

Chemokines also seem to have effect on the association between endometriosis and infertility. An increase of chemokines in peritoneal fluid of patients with endometriosis would have effect on sperm by decreasing its mobility and its concentration.

The increase in some inflammatory cytokines and chemokines may be responsible for various pain symptoms of endometriosis and even infertility. Although the pathogenesis underlying the development of endometriosis is unknown, there is substantial evidence that chemokines play innumerous roles in the pathogenesis and development of this disease and infertility associated with it. Additional studies evaluating the role of each chemokine along with clinical trials can contribute to a better understanding of the pathogenesis of this disease, as well as be useful in developing a noninvasive diagnosis and feasible therapeutic in the future.

Keywords: Endometriosis; Chemokine; Pathogenesis; Immunology; Cytokine


Endometriosis is a common gynecological condition that affects 10 to 15% of women in their reproductive period, and up to 50% of women with chronic pelvic pain and/or infertility [1,2]. It has been regarded as one of the leading causes of gynecological hospitalization [3]. The disease is defined by stroma and/or endometrial glandular epithelium implant in extra-uterine location [4], and is likely to compromise several sites, including ovaries, peritoneum, uterosacral ligaments, retro-cervical region, rectum-sigmoid colon, terminal ileum, appendix, bladder and ureters [3,5-8].

In spite of being one of the most studied diseases in gynecology [9], some aspects of it still remain unclear, especially its etiology [7,8]. Two etiopathogenic hypotheses have prevailed since a century ago: the theories of coelomic metaplasia [10] and retrograde menstruation [11]. The latter may take into account the influence of a favorable hormonal environment and immunological factors on the failure to eliminate endometrial cells from the peritoneal cavity [12,13]. Cells that fall into the endometrial cavity should probably trigger a local immune response. On this regard, the balance between immunity and tolerance is crucial for maintaining immune homeostasis in which many mechanisms are involved in keeping the immune response under control, including the activity of Natural Killer (NK) and T-regulatory (T-reg) cells [14-16]. As in cancer and others autoimmune diseases, chemokines seems to play a key role in immune balance by modulating the activity of inflammatory mediators and allowing the maintenance and progression of these diseases. Likewise, in endometriosis, this role appears to be essential and have been the result of study by many authors in the last few years.

In this review, we will address the complexity and challenges of determining the usual behaviour of chemokines in endometriosis.

Methods of Review

A systematic review was conducted in MEDLINE (1966-2012) and PubMed (1966-2012), using endometriosis and chemokines as MeSH (Medical Subject Headings) terms. The abstracts of all articles were read and the manuscripts thoroughly reviewed. The references in all articles were also reviewed for additional information. The articles were selected and reviewed independently by 2 reviewers (PB and SP) to warrant quality.

The search engine returned 233 articles of which 164, published within the last 10 years, were selected. Of these, we excluded all articles that did not correlate chemokines directly in the pathogenesis of endometriosis and those that were not published in English. Besides, we selected those that had a significant sample with proper review, Meta-analyzes and controlled studies, accounting for 44 articles. While reviewing the references of articles, we selected other 13 articles, published more than 10 years ago, but relevant to our review for being pioneering articles.


Chemokines are a large family of structurally homologous cytokines with approximately 8 to 12kD, called chemotactic cytokines, as they stimulate the movement of leukocytes (chemokinesis), and regulate the migration of blood cells to the tissues (chemotaxis) [17].

The chemokine molecules have two internal disulfide loops and are divided into four subfamilies according to the position of their amino terminals cysteine residues: two cysteines directly adjacent (CC), two cysteines separated by one amino acid (CXC), two cysteines separated by three amino acids (C3XC), and finally, the fourth subfamily (XCL1) with a single cysteine (International Union of Immunological Societies/World Health Organization Nomenclature Subcommittee on Chemokine) [18]. In the standardized nomenclature, all chemokines carry an “L“suffix to characterize them as ligands and all receptors use an “R” suffix with the same purpose [19].

Chemokines act through high affinity trans-membrane receptors exposed on the surface of circulating cells. Eleven different receptors for CC chemokines (called CCR1 until CCR11) and six for CXC chemokines (called CXCR1 until CXCR6) were identified [20,21]. Although chemokine receptors have binding sites that may be highly specified (CCR9, CXCR6), as a rule, the same receptor may be the target of binding for various chemokine in the same group (Table 1) [22].

Citation: Bellelis P, Abrao MS, Baracat EC and Podgaec S. Chemokines Modulate the Activity of Several Cells of the Immune System: Relationship with the Pathogenesis of Endometriosis. Austin J Reprod Med Infertil. 2015; 2(6): 1032. ISSN:2471-0393