Abstract
Objective. Acute pyelonephritis is one of the most frequent medical complications of pregnancy, as well as a common cause of antepartum hospitalization. Interferon (IFN)-γ inducible protein, CXCL10/IP-10, is a member of the CXC chemokine family with pro-inflammatory and anti-angiogenic properties. The purpose of this study was to determine whether maternal serum concentrations of CXCL10/IP-10 change in patients with acute pyelonephritis during pregnancy.
Study design. This cross-sectional study was conducted to determine the difference in maternal serum concentrations of CXCL10/IP-10 in pregnant women with acute pyelonephritis (N = 41) and normal pregnant women (N = 89). Pyelonephritis was defined in the presence of a positive urine culture, fever, and maternal clinical signs; blood cultures were performed in 36 cases. Maternal serum concentrations of CXCL10/IP-10 were measured by a sensitive immunoassay. Non-parametric statistics were used for analysis.
Results. (1) The median serum concentration of CXCL10/IP-10 in pregnant patients with pyelonephritis was significantly higher than in normal pregnant women (median 318.5 pg/mL, range 78.8–2459.2 vs. median 116.1 pg/mL, range 40.7–1314.3, respectively; p < 0.001); (2) maternal median serum concentrations of CXCL10/IP-10 did not differ significantly among patients with acute pyelonephritis with and without bacteremia (positive blood cultures: median 362.6 pg/mL, range 100.2–2459.2 vs. negative blood cultures: median 298.9 pg/mL, range 108.5–1148.7, respectively; p = 0.3).
Conclusions. Pyelonephritis in pregnant women is associated with an increased maternal serum concentration of the chemokine CXCL10/IP-10.
Introduction
Acute pyelonephritis is one of the most frequent medical complications in pregnancy Citation[1], and a common cause of antepartum hospitalization Citation[2], with most of the cases occurring during the second trimester Citation[3]. Complications following an event of acute pyelonephritis during pregnancy include anemia Citation[3-5], transient renal dysfunction Citation[3], preterm labor Citation[1],Citation[6], sepsis Citation[3],Citation[7], and septic shock Citation[7-11]. Moreover, pregnant women with pyelonephritis are at increased risk of developing acute respiratory distress syndrome (ARDS) Citation[12-14].
The human interferon-inducible protein 10 (IP-10 or CXCL10) is a chemokine of the CXC family Citation[15]. A unique feature of some members of this type of chemokine is that they have pro-inflammatory properties and act as modulators of angiogenesis in conditions such as wound healing, ischemia, and neoplasia. These dual properties are related to the shared expression of specific chemokine receptors by leukocytes and endothelial cells Citation[16-27].
IP-10 is inducible by pro-inflammatory stimuli such as interferon-γ (IFN-γ) Citation[28-39], tumor necrosis factor-α (TNF-α) Citation[37],Citation[40-46], viruses, and microbial products Citation[33],Citation[37],Citation[47-52], either directly or through nuclear factor-κB (NF-κB) Citation[48],Citation[49],Citation[53-56]. It has been proposed that this chemokine is also involved in the recruitment and potentiation of T helper 1 (Th1) responses Citation[57-59].
The objective of this study was to determine whether the maternal serum concentrations of IP-10 are different in normal pregnancies and pregnant women with acute pyelonephritis.
Methods
Study design
This cross-sectional study included normal pregnant women (N = 89) and pregnant patients with acute pyelonephritis (N = 41). Patients were considered to have a normal pregnancy if they met the following criteria: (1) no medical, obstetrical, or surgical complications, (2) absence of labor at the time of venipuncture, and (3) delivery of a normal term (≥37 weeks) infant whose birth weight was between the 10th and 90th percentile for gestational age Citation[60]. Acute pyelonephritis was diagnosed in the presence of fever (temperature ≥38°C), clinical signs or symptoms of upper urinary infection (e.g., flank pain, costovertebral angle tenderness), pyuria, and a positive urine culture. Blood cultures were performed in 36 patients with pyelonephritis.
Patients were enrolled at the Detroit Medical Center/Hutzel Women's Hospital, MI, USA. All provided written informed consent for the collection of clinical data and biological materials under protocols approved by the Institutional Review Boards of both Wayne State University and the National Institute of Child Health and Human Development of the National Institute of Health (NIH/DHHS). Many of these samples have been employed to study the biology of inflammation (i.e., complement, flow cytometry), hemostasis, angiogenesis regulation, and growth factor concentrations in normal pregnant women and those with complications. Samples from these patients have been used for other studies of the biology of pyelonephritis and inflammation.
IP-10 (CXCL10) determinations
A specific and sensitive enzyme-linked immunoassay was used to determine concentrations of CXCL10/IP-10 in human maternal serum. Immunoassays for CXCL10/IP-10 were obtained from R&D Systems (Minneapolis, MN, USA). Briefly, maternal serum samples were incubated in duplicate wells of the microtiter plates, pre-coated with monoclonal antibodies specific for CXCL10/IP-10. During this incubation step, any IP-10 present in the standards or maternal serum is bound by the immobilized antibodies. After repeated washing and aspiration to remove all unbound substances, an enzyme-linked polyclonal antibody specific for CXCL10/IP-10 was added to the wells. Following a wash to remove excess and unbound materials, a substrate solution was added to the wells and color developed in proportion to the amount of CXCL10/IP-10 bound in the initial step. The color development was stopped with the addition of an acid solution and the intensity of color was read using a programmable spectrophotometer (SpectraMax M2, Molecular Devices, Sunnyvale, CA, USA). The concentrations of IP-10 in serum samples were determined by interpolation from individual standard curves composed of recombinant human CXCL10/IP-10. The calculated inter- and intra-assay coefficients of variation (CVs) for CXCL10/IP-10 immunoassays in our laboratory were 7.99% and 4.12%, respectively. The lower limit of detection (sensitivity) was calculated to be 5.01 pg/mL.
Statistical analysis
The Kolmogorov–Smirnov test was employed to determine whether the data were normally distributed. Comparisons among groups were performed using the Mann–Whitney test. A p-value of <0.05 was considered statistically significant. The statistical package used was SPSS v.14.0 (SPSS Inc., Chicago, IL, USA).
Results
Clinical and obstetrical characteristics of women in each group are displayed in . The median serum concentration of CXCL10/IP-10 was significantly higher in pregnant patients with acute pyelonephritis than in normal pregnant women (acute pyelonephritis: median 318.5 pg/mL, range 78.8–2459.2 vs. normal pregnancy: median 116.1 pg/mL, range 40.7–1314.3; p < 0.001) ().
Figure 1. Maternal serum concentrations of CXCL10/IP-10 in patients with normal pregnancies and those with pyelonephritis. The median serum concentration of CXCL10/IP-10 in pregnant patients with pyelonephritis was significantly higher than in normal pregnant women (median 318.5 pg/mL, range 78.8–2459.2 vs. median 116.1 pg/mL, range 40.7–1314.3, respectively; p < 0.001).
Table I. Clinical and obstetrical characteristics of the study groups
The most common microorganism isolated from urine cultures of patients with pyelonephritis was Escherichia coli (30 cases). Other microorganisms less frequently isolated included mixed flora (2), Klebsiella pneumoniae (2), E. coli and Streptococcus viridans (1), Enterobacter aerogenes (1), Pseudomonas aeruginosa (1), Gram-negative bacilli (1), Proteus mirabilis (1), Streptococcus agalactiae (1), and Citrobacter koseri (1).
Among the 36 women with acute pyelonephritis in which blood cultures were performed, the results were positive in 16 cases (44.4%). The following microorganisms were isolated: E. coli (11), coagulase negative Staphylococcus (2), Gram-positive cocci (1), Klebsiella pneumoniae (1), and Enterobacter aerogenes (1).
Among patients with acute pyelonephritis, no significant difference in the median serum concentration of CXCL10/IP-10 was observed between those who had positive blood cultures and those who did not (positive blood cultures: median 362.6 pg/mL, range 100.2–2459.2 vs. negative blood cultures: median 298.9 pg/mL, range 108.5–1148.7, respectively; p = 0.3) ().
Figure 2. Maternal serum concentrations of CXCL10/IP-10 in patients with pyelonephritis. No significant differences in maternal median serum concentrations of CXCL10/IP-10 were observed between patients with positive and negative blood cultures (median 362.6 pg/mL, range 100.2–2459.2 vs. median 298.9 pg/mL, range 108.5–1148.7, respectively; p = 0.3).
Patients with acute pyelonephritis delivered neonates with a lower birth weight than those in the control group (pyelonephritis: median 3140 g, range 1080–4090 g vs. normal pregnancy: median 3342 g, range 2550–4050 g; p = 0.02). However, the mean gestational age at delivery was not different between the two groups.
Discussion
Principal findings of this study
(1) The median serum concentration of CXCL10/IP-10 in pregnant women with acute pyelonephritis was significantly higher than that of normal pregnant women; (2) among patients with pyelonephritis, no significant difference in the median serum concentration of CXCL10/IP-10 was observed between those who had positive blood cultures and those who did not. This is the first report documenting an increase in the maternal serum concentration of CXCL10/IP-10 in women with an acute infection during pregnancy.
The chemokine family
The superfamily of chemokines includes secreted proteins with a molecular weight of 8–10 kD that selectively target and activate specific cell populations and attract them to inflamed tissues in which microbial invasion has occurred Citation[19],Citation[20],Citation[22],Citation[61],Citation[62].
Until recently, there was much discussion about the specificity of subsets of chemokines for a particular leukocyte population (e.g., neutrophils, lymphocytes, etc.), and whether or not a particular set of chemokines was involved in the disease processes with a characteristic type of white blood cell infiltration. Recent findings indicate that chemokines and their receptors are expressed by a wide variety of cells of non-hematopoietic origin, and that the functions of chemokines extend far beyond white blood cell attraction. A fundamental observation, which has added complexity to the field, is the ‘promiscuity’ of this family of molecules and their receptors. Indeed, chemokines can bind several different receptors, while chemokine receptors can bind more than one chemokine Citation[19].
Traditionally, two main subfamilies of chemokines have been described on the basis of the number and arrangement of the conserved cystine residues, the CC and the CXC chemokines Citation[19],Citation[20],Citation[22],Citation[61],Citation[62]. The CC chemokines preferentially attract monocytes, basophils, eosinophils, and lymphocytes, but have no effect on neutrophils Citation[63]. The CXC chemokines are subdivided according to the presence or absence of the glutamic acid–leucine–arginine (ELR) sequence. ELR-containing CXC chemokines (ELR+) are chemotactic for neutrophils and promoters of angiogenesis. In contrast, non-ELR containing CXC chemokines (ELR−) are chemotactic mainly for lymphocytes, and characterized by anti-angiogenic activity Citation[21],Citation[23-26],Citation[64],Citation[65].
The chemokine CXCL10/IP-10
IP-10 (CXCL10) is an ELR− CXC chemokine Citation[15] first described as the product of a gene induced in response to recombinant IFN-γ in several cell populations Citation[28].
The biological properties of IP-10 are mediated through the interaction with a trans-membrane G protein-coupled receptor, CXCR3 Citation[66],Citation[67], shared by two other IFN-γ-inducible CXC chemokines, CXCL9 (MIG) and CXCX11 (ITAC), whose distinct biological activities are related to different signal transduction pathways Citation[68-71].
CXCL10/IP-10 gene and protein expression is modulated by pro-inflammatory stimuli. Indeed, IFN-γ is an inducer of the gene and protein expression of this chemokine by mononuclear cells Citation[28], neutrophils Citation[36],Citation[37], eosinophils Citation[37],Citation[72], keratinocytes Citation[28],Citation[31],Citation[32],Citation[34], fibroblasts Citation[28], endothelial cells Citation[28-30], pancreatic β cells Citation[38],Citation[39], and animal astrocytes/microglia Citation[33],Citation[35]. TNF-αCitation[37],Citation[40-46], interleukin (IL)-1βCitation[37],Citation[38], as well as viral Citation[33],Citation[48],Citation[49] and microbial products Citation[37],Citation[47],Citation[50-52], can also stimulate the production of IP-10. Interestingly, in vitro infection of epithelium of the urinary tract with E. coli results in an increase (as measured in the conditioned media with ELISA) in both CXCL10/IP-10 secretion and epithelial cell CXCL10/IP-10 mRNA expression Citation[73]. Activation of the NF-κB pathway Citation[48],Citation[49],Citation[53-56] after ligation of pattern recognition receptors (TLR4 Citation[50] and TLR3 Citation[56]) can also upregulate gene and protein expression of IP-10. Thus, IP-10 is considered an ‘NF-κB responsive gene’Citation[74].
IP-10 in inflammation
The pro-inflammatory activities of CXCL10/IP-10 include chemotaxis and endothelial adhesion of activated T cells Citation[75], as well as chemotaxis Citation[76] and enhancement of natural killer (NK) cell-mediated cytolysis Citation[76]. However, this chemokine is a poor neutrophil activator Citation[75],Citation[77], and its effects on monocytes Citation[66],Citation[75] and B cells Citation[78],Citation[79] are a matter of controversy.
Serum IP-10 in the presence of infections
Infection is associated with an increase in serum and/or plasma concentrations of CXCL10/IP-10. Evidence in support of this statement includes: (1) median serum concentrations of CXCL10/IP-10, determined on the first postnatal day, are significantly higher in neonates with perinatal infections than in controls (p < 0.001) Citation[80]; (2) median serum concentrations of CXCL10/IP-10 are significantly higher in neonates with nosocomial infections as compared to controls Citation[80]; (3) neonatal plasma IP-10 ≥1250 pg/mL has been reported to identify all preterm infants with sepsis and necrotizing enterocolitis Citation[81]; (4) it has been proposed that the severity of neonatal infection is associated with the magnitude of upregulation of circulating CXCL10/IP-10 (indeed, CXCL10/IP-10 plasma concentrations in infants who died of sepsis were all markedly elevated (range 23 817–34 415 pg/mL)) Citation[81]; and (5) in adults, plasma CXCL10/IP-10 concentration has been used to monitor the disease activity and the response to therapy of Mycobacterium tuberculosis infection Citation[82].
Interestingly, serum concentrations of CXCL10/IP-10 have been reported to be significantly higher in those with severe ARDS than in control patients (patients with bacterial pneumonia). Chemokine and cytokine dysregulation has been implicated in the pathogenesis of ARDS Citation[81],Citation[83],Citation[84], and CXCL10/IP-10 has been proposed as a useful marker of lung injury in patients with severe acute respiratory syndrome (SARS) Citation[85].
IP-10 in urinary tract infections
Previous studies have reported higher serum Citation[86] and urine Citation[86],Citation[87] CXCL10/IP-10 concentrations (determined by ELISA) in the presence of both culture-proven Gram-negative urosepsis Citation[86] and febrile urinary tract infections than in control patients Citation[73],Citation[87]. Furthermore, serum CXCL10/IP-10 concentrations did not change significantly during the follow-up (72 h after beginning of treatment). However, a significant decrease in the urinary concentrations was observed Citation[86]. In serum and in urine, CXCL10/IP-10 concentrations were not different in patients with positive or negative blood cultures Citation[86],Citation[87]. Of interest is that in experimental endotoxemia in humans, CXCL10/IP-10 concentrations were elevated in both serum and urine Citation[86]. The finding of increased concentrations in urine raises questions about how the changes in the peripheral circulation are reflected in urine. It is possible that this reflects renal excretion of increased available CXCL10/IP-10 in the peripheral circulation, local production, or both.
IP-10: Maternal serum concentrations increase in pregnancies complicated with pyelonephritis
This is the first report on the topic of serum CXCL10/IP-10 concentrations in pregnant women with pyelonephritis. Our finding that pyelonephritis in pregnancy is associated with a significant increase in the serum concentration of this chemokine is consistent with what has been previously reported in non-pregnant patients Citation[86]. The mechanisms responsible for the increase in CXCL10/IP-10 during normal pregnancy Citation[88] and in acute infection during gestation are unknown. In addition, the physiologic function of CXCL10/IP-10 during pregnancy as well as the role of CXCL10/IP-10 in acute infection during gestation remain to be determined. Recently, it has been demonstrated that CXCL10/IP-10 has antimicrobial properties Citation[89]. Thus, it is tempting to postulate that this chemokine participates in host defense not only by orchestrating leukocyte chemotaxis, but also by inducing other biological activities that may have a protective effect during infection. In this study, no significant differences were observed in the median maternal serum concentrations of CXCL10/IP-10 between patients with and without positive blood cultures. Otto et al. Citation[87] reported similar results when quantifying urinary CXCL10 in response to febrile urinary tract infections. Indeed, only some chemokines such as CXCL1, CXCL3, CXCL5, CXCL8, and CCL2, but not CXCL10/IP-10, were significantly higher in the presence of bacteremia. One interpretation is that the elevation in the serum concentration of CXCL10/IP-10 in the context of pyelonephritis results from systemic inflammation and it is not affected by the presence of microorganisms in the circulation. However, one possible explanation for this negative result is a limited statistical power.
IP-10: A local first line defense mechanism in the urinary tract mucosae
Migration of immunocompetent cells to sites of mucosal infection requires expression of molecules by the epithelial cells of the affected tissues Citation[90]. Chemokines, particularly those belonging to the CXC family, have been shown to play an important role in this process Citation[20],Citation[90-94]. Indeed, infections of the mucosae are associated with a local increase in CXCL10/IP-10. Evidence in support of this statement includes: (1) exposure of uroepithelial cells to E. coli is followed by a significant increase in CXCL10/IP-10 mRNA expression (quantification with an RNA protection assay) and protein secretion (ELISA) Citation[73]; (2) intravesical instillation of Mycobacterium bovis bacillus Calmette–Guerin (BCG) is followed by detection of urinary CXCL10/IP-10 in patients undergoing immunotherapy for bladder cancer (by ELISA) Citation[95],Citation[96]; (3) conditioned media collected from culture of human uroepithelial cell lines exposed to BCG or BCG-derived cytokines such as IFN-γ, IL-1β, and TNF-α contains a significantly higher amount of CXCL10/IP-10 (ELISA) than control media Citation[95]; and (4) intrapulmonary administration of K. pneumoniae in mice is followed by upregulation of CXCL10/IP-10 mRNA expression in the lung. Moreover, neutralization of CXCL10/IP-10 activity with an antibody results in reduced bacterial clearance and decreased survival, while in contrast, over-expression of CXCL10/IP-10 (via adenovirus) results in improved bacterial clearance Citation[97].
Antimicrobial activity of IP-10
Recent studies have reported structural similarities between chemokines and defensins (a family of antimicrobial peptides serving as the first line of defense in epithelia before the activation of adaptive immunity) Citation[98-105]. The following evidence suggests an overlap between the biological functions of defensins and CXCL10/IP-10: (1) chemokines share many properties with defensins such as structure, size, charge, disulfide bonding, and IFN-inducibility Citation[89]; (2) the CXC motif, present in CXCL10/IP-10, is contained and conserved in α-defensins-1 and -2; these defensins, as well as a structurally-related β-defensin, have been shown to be chemotactic for leukocytes at subnanomolar concentrations Citation[106-109]; (3) CXCL10/IP-10 has antimicrobial properties similar to those of defensins: in a radial diffusion assay, CXCL10/IP-10 has been demonstrated to have antimicrobial activity against E. coli and Listeria monocytogenesCitation[89]. Moreover, this antimicrobial activity, similarly to the activity of defensins and many other antimicrobial peptides Citation[110], is salt-dependent (inhibited by NaCl) Citation[89]; and (4) calculations of the amount of CXCL10/IP-10 produced by infiltrating inflammatory cells indicate that the tissue concentrations of this chemokine may reach the threshold necessary for microbicidal activity locally, and directly inactivate microbes before attracting other host defense cells to the area Citation[89].
IP-10, pyelonephritis, and lung injury
Compared to non-pregnant subjects with pyelonephritis, mothers with pyelonephritis are at an increased risk for ARDS Citation[7],Citation[12-14],Citation[111-115]. This has been attributed to an enhanced baseline activation of the innate immunoresponse during pregnancy Citation[116],Citation[117], although other explanations may be possible Citation[118]. Indeed, an excessive inflammatory response (in particular neutrophil activation) has been implicated in the pathogenesis of ARDS Citation[119]. Nevertheless, the precise mechanism for the association between pyelonephritis and ARDS remains to be determined. Neumann et al. Citation[119] caused lung injury in female mice by inducing continuous leakage of bacteria into the peritoneal cavity. The investigators demonstrated that this procedure causes, in as early as 3 hours, massive recruitment of granulocytes to the lung and a significant increase in lung CXCL10/IP-10 mRNA. The authors concluded that CXCL10/IP-10 may contribute to the accumulation of mononuclear phagocytes in the lung Citation[119]. Thus, CXCL10/IP-10 may be involved in the pathogenesis of ARDS in pregnant women with sepsis and/or pyelonephritis. This hypothesis is strengthened by the observation that in patients with SARS the serum concentrations of CXCL10/IP-10 increase before the development of chest involvement, reaching a peak concentration before abnormalities are detected in the chest X-ray Citation[85].
Conclusion
Maternal serum concentrations of CXCL10/IP-10 are higher in the context of acute bacterial infection (pyelonephritis) than in normal pregnancy. The role of this chemokine in host defense during infection requires further study.
Acknowledgements
This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, NIH, DHHS.
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