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The Journal of Maternal-Fetal & Neonatal Medicine Volume 20, 2007 - Issue 11
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Original Article

CXCL10/IP-10: A missing link between inflammation and anti-angiogenesis in preeclampsia?

Francesca Gotsch Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA
,
Roberto Romero Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USACorrespondence[email protected]
, MD,
Lara Friel Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA; Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, Michigan, USA
,
Juan Pedro Kusanovic Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA
,
Jimmy Espinoza Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA; Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, Michigan, USA
,
Offer Erez Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA
,
Nandor Gabor Than Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA
,
Pooja Mittal Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA; Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, Michigan, USA
,
Samuel Edwin Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA
,
Bo Hyun Yoon Seoul National University College of Medicine, Department of Obstetrics and Gynecology, Seoul, South Korea
,
Chong Jai Kim Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA; Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, USA
,
Shali Mazaki-Tovi Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA; Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, Michigan, USA
,
Tinnakorn Chaiworapongsa Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA; Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, Michigan, USA
&
Sonia S. Hassan Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland, and Detroit, Michigan, USA; Department of Obstetrics and Gynecology, Wayne State University/Hutzel Women's Hospital, Detroit, Michigan, USA
 show all
Pages 777-792 | Received 29 Jan 2007, Accepted 02 May 2007, Published online: 07 Jul 2009

Abstract

Objective. Interferon (IFN)-γ inducible protein, CXCL10/IP-10, is a member of the CXC chemokine family with pro-inflammatory and anti-angiogenic properties. This chemokine has been proposed to be a key link between inflammation and angiogenesis. The aim of this study was to determine whether preeclampsia and delivery of a small for gestational age (SGA) neonate are associated with changes in maternal serum concentration of CXCL10/IP-10.

Study design. This cross-sectional study included patients in the following groups: (1) non-pregnant women (N = 49); (2) women with normal pregnancies (N = 89); (3) patients with preeclampsia (N = 100); and (4) patients who delivered an SGA neonate (N = 78). SGA was defined as birth weight below the 10th percentile. Maternal serum concentrations of CXCL10/IP-10 were measured by sensitive immunoassay. Non-parametric statistics were used for analysis.

Results. (1) Patients with normal pregnancies had a significantly higher median serum concentration of CXCL10/IP-10 than non-pregnant women (median 116.1 pg/mL, range 40.7–1314.3 vs. median 90.3 pg/mL, range 49.2–214.7, respectively; p = 0.002); (2) no significant correlation was found between maternal serum concentration of CXCL10/IP-10 and gestational age (between 19 and 38 weeks); (3) there were no differences in median serum CXCL10/IP-10 concentrations between patients who delivered an SGA neonate and those with normal pregnancies (median 122.4 pg/mL, range 37.3–693.5 vs. median 116.1 pg/mL, range 40.7–1314.3, respectively; p > 0.05); (4) patients with preeclampsia had a higher median serum concentration of CXCL10/IP-10 than normal pregnant women (median 156.4 pg/mL, range 47.4–645.9 vs. median 116.1 pg/mL, range 40.7–1314.3, respectively; p < 0.05); (5) patients with preeclampsia had a higher median concentration of CXCL10/IP-10 than those who delivered an SGA neonate (median 156.4 pg/mL, range 47.4–645.9 vs. median 122.4 pg/mL, range 37.3–693.5, respectively; p < 0.05).

Conclusions. Patients with preeclampsia have significantly higher serum concentrations of CXCL10/IP-10 than both normal pregnant women and mothers who have SGA neonates. These results are likely to reflect an anti-angiogenic state as well as an enhanced systemic inflammatory response in patients with preeclampsia. Alternatively, since preeclampsia and SGA share several mechanisms of disease, it is possible that a higher concentration of this chemokine may contribute to the clinical presentation of preeclampsia in patients with a similar intrauterine insult.

Introduction

Patients with preeclampsia and those with a small for gestational age (SGA) neonate share a number of pathophysiological characteristics including: (1) abnormal physiologic transformation of the spiral arteries Citation[1-8]; (2) chronic uteroplacental ischemia Citation[9-16]; (3) endothelial cell dysfunction Citation[17-24]; (4) an anti-angiogenic state Citation[25-32]; and (5) intravascular inflammation Citation[18],Citation[33-37]. Furthermore, a biased Th1/Th2 (T-helper 1/T-helper 2) balance towards a Th1 response has been reported in preeclampsia Citation[38-46] and SGA Citation[47].

The human interferon-inducible protein 10 (IP-10 or CXCL10) is a chemokine of the CXC family Citation[48]. A unique feature of members of this chemokine family 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[49-60].

IP-10 is inducible by pro-inflammatory stimuli such as interferon-γ (IFN-γ) Citation[61-72], tumor necrosis factor-α (TNF-α) Citation[70],Citation[73-79], viruses, and microbial products Citation[66],Citation[70],Citation[80-85], directly or through activation of nuclear factor-kappa B (NF-kB) Citation[81],Citation[82],Citation[86-89]. It has been proposed that this chemokine is also involved in recruitment and potentiation of Th1 responses as well as in the pathogenesis of allograft rejection Citation[90-103], multiple sclerosis Citation[104-108], diabetes mellitus type 1 Citation[109],Citation[110], Graves' disease Citation[111-114], autoimmune thyroiditis Citation[115],Citation[116], pulmonary fibrosis Citation[117-119], and cardiovascular diseases such as atherosclerosis Citation[120] and coronary syndromes Citation[121],Citation[122]. Importantly, IP-10 has potent anti-angiogenic activity, both in vitro and in vivoCitation[123-126].

The balance between angiogenic and anti-angiogenic (angiostatic) factors controlled by molecules involved in inflammatory processes may have an impact on the pathogenesis of many diseases Citation[54],Citation[58].

We propose that IP-10 is involved in the pathophysiology of preeclampsia because this condition is characterized by intravascular inflammation and an anti-angiogenic state. The objective of this study was to compare the maternal serum IP-10 concentrations in normal pregnancy, preeclampsia, and SGA.

Methods

Study design

This retrospective cross-sectional study included patients with preeclampsia (N = 100), women who delivered an SGA neonate (N = 78), normal pregnant women (N = 89), and non-pregnant women (N = 49). All patients were enrolled at Hutzel Hospital, Detroit, MI, USA. All women 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 previously employed to study the biology of inflammation, hemostasis, angiogenesis regulation, and growth factor concentrations in non-pregnant women, normal pregnant women, and those with pregnancy complications.

Preeclampsia was defined in the presence of hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg on at least two occasions, 4 hours to 1 week apart, after the 20th week of gestation) and proteinuria (≥300 mg in a 24-hour urine collection, or two random urine specimens obtained 4 hours to 1 week apart containing ≥1+ protein by dipstick Citation[127],Citation[128] or one dipstick measurement ≥2+) Citation[129]. Severe preeclampsia was diagnosed according to the criteria proposed by the American College of Obstetricians and Gynecologists (ACOG) committee Citation[128]. Patients with preeclampsia were sub-classified as either early-onset (<34 weeks) or late onset (≥34 weeks) disease according to the gestational age at which preeclampsia was diagnosed. A neonate was defined as SGA when the birth weight was below the 10th percentile for gestational age according to the reference range proposed by Alexander et al. Citation[130]. 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[130]. The non-pregnant group consisted of healthy volunteers not taking oral contraceptives whose blood was drawn in the secretory phase of the menstrual cycle.

IP-10 (CXCL10) determinations

Specific and sensitive enzyme-linked immunoassays were used to determine concentrations of IP-10 in human maternal serum. Immunoassays for 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 a monoclonal antibody specific for 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 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 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 IP-10. The calculated inter- and intra-assay coefficients of variation for 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 used to determine whether the data were normally distributed. The Spearman's correlation test was used in assessing the relationship between maternal serum concentration of IP-10 and gestational age at blood draw in patients with normal pregnancies. Comparisons among groups were performed using Kruskal–Wallis tests with post-hoc analysis for continuous variables, and Chi-square or Fisher's exact test for categorical variables. A p value <0.05 was considered statistically significant. The statistical package used was SPSS v.12.0 (SPSS Inc., Chicago, IL, USA).

Results

Three hundred sixteen patients were included in this study. The demographic and clinical characteristics of the study groups are displayed in .

Table I.  Clinical and obstetrical characteristics of the study groups.

Among patients with preeclampsia, 63% (63/100) were classified as early-onset and 88% (88/100) as severe preeclampsia. In 75.6% (59/78) of patients who delivered an SGA neonate, the birth weight was below the 5th percentile. IP-10 was detectable in the serum of all subjects.

Serum concentration of IP-10 in pregnancy

Patients with normal pregnancies had a significantly higher median serum concentration of IP-10 than non-pregnant women (median 116.1 pg/mL, range 40.7–1314.3 vs. median 90.3 pg/mL, range 49.2–214.7, respectively; p = 0.002) (see ). There was no significant correlation between maternal serum IP-10 concentration and gestational age at blood draw (r = 0.039; p = 0.7).

Figure 1. Serum concentrations of CXCL10/IP-10 in non-pregnant women and in patients with normal pregnancies. Patients with normal pregnancies had a significantly higher median serum concentration of IP-10 than non-pregnant women (median 116.1 pg/mL, range 40.7–1314.3 vs. median 90.3 pg/mL, range 49.2–214.7, respectively; p = 0.002).

Figure 1. Serum concentrations of CXCL10/IP-10 in non-pregnant women and in patients with normal pregnancies. Patients with normal pregnancies had a significantly higher median serum concentration of IP-10 than non-pregnant women (median 116.1 pg/mL, range 40.7–1314.3 vs. median 90.3 pg/mL, range 49.2–214.7, respectively; p = 0.002).

IP-10 in preeclampsia

Patients with preeclampsia had a higher median serum concentration of IP-10 than normal pregnant women and those who delivered an SGA neonate (preeclampsia: median 156.4 pg/mL, range 47.4–645.9; normal pregnancy: median 116.1 pg/mL, range 40.7–1314.3; SGA: median 122.4 pg/mL, range 37.3–693.5; p < 0.05 for both comparisons). In contrast, there were no significant differences in the maternal serum median IP-10 concentrations between patients who delivered an SGA neonate and those with normal pregnancies (SGA: median 122.4 pg/mL, range 37.3–693.5 vs. normal pregnancy: median 116.1 pg/mL, range 40.7–1314.3; p > 0.05) (see ).

Figure 2. Maternal serum concentrations of CXCL10/IP-10 among the study groups. Patients with preeclampsia had a significantly higher median serum concentration of IP-10 than normal pregnant women (median 156.4 pg/mL, range 47.4–645.9 vs. median 116.1 pg/mL, range 40.7–1314.3, respectively; p < 0.05) and than patients who delivered a small for gestational age (SGA) neonate (median 156.4 pg/mL, range 47.4–645.9 vs. median 122.4 pg/mL, range 37.3–693.5, respectively; p < 0.05). No significant differences were found in maternal serum median IP-10 concentrations between patients who delivered an SGA neonate and those with normal pregnancies (median 122.4 pg/mL, range 37.3–693.5 vs. median 116.1 pg/mL, range 40.7–1314.3, respectively; p > 0.05).

Figure 2. Maternal serum concentrations of CXCL10/IP-10 among the study groups. Patients with preeclampsia had a significantly higher median serum concentration of IP-10 than normal pregnant women (median 156.4 pg/mL, range 47.4–645.9 vs. median 116.1 pg/mL, range 40.7–1314.3, respectively; p < 0.05) and than patients who delivered a small for gestational age (SGA) neonate (median 156.4 pg/mL, range 47.4–645.9 vs. median 122.4 pg/mL, range 37.3–693.5, respectively; p < 0.05). No significant differences were found in maternal serum median IP-10 concentrations between patients who delivered an SGA neonate and those with normal pregnancies (median 122.4 pg/mL, range 37.3–693.5 vs. median 116.1 pg/mL, range 40.7–1314.3, respectively; p > 0.05).

Among patients with preeclampsia, no significant differences in serum concentrations of IP-10 were observed between patients with early onset and late onset disease (early onset preeclampsia: median 155.6 pg/mL, range 47.5–645.9 vs. late onset preeclampsia: median 165.2 pg/mL, range 64.7–401.1; p = 0.4). Similarly, there were no significant differences between mild and severe preeclampsia (mild preeclampsia: median 177.7 pg/mL, range 79.4–401.1 vs. severe preeclampsia: median 155.5 pg/mL, range 47.5–645.9; p = 0.56).

Among patients who delivered an SGA neonate, there were no significant differences in serum concentrations of IP-10 between patients who delivered a neonate with a birth weight at <5th percentile and those who delivered a neonate with a birth weight between the 5th and 9th percentile (SGA <5th percentile: median 126.7 pg/mL, range 37.3–693.5 vs. SGA 5th–9th percentile: median 108.7 pg/mL, range 40.7–349.5; p = 0.2).

Using analysis of covariance (ANCOVA), only diagnostic groups but not storage time had a significant effect on the serum concentrations of CXCL10 (storage time: p = 0.5; diagnostic groups: p < 0.001). Storage time did not have a significant effect on the serum concentrations of CXCL10 even when gestational age at blood draw was included in the analysis (storage time: p = 0.72; diagnostic groups: p = 0.02; gestational age at blood draw: p = 0.5).

Discussion

Principal findings of this study

(1) The median serum concentration of IP-10 in normal pregnancy was higher than that of non-pregnant women; (2) there was no relationship between gestational age and the maternal serum concentration of IP-10; (3) preeclampsia, but not SGA, was associated with a higher median concentration of maternal serum IP-10. These results are novel and suggest that IP-10 may participate in the pathophysiology of preeclampsia.

What is CXCL10/IP-10?

IP-10 (CXCL10) is a chemokine of the CXC family Citation[48], which was first described as the product of a gene induced in response to recombinant IFN-γ in several cell populations, including U937 histiocytic lymphoma, human fibroblasts, mononuclear and endothelial cells Citation[61]. The principal biological activity of chemotactic cytokines, such as IP-10, is regulation and control of the basal homeostatic and inflammatory leukocyte movement Citation[57].

In addition, IP-10 has potent anti-angiogenic properties Citation[54],Citation[56],Citation[57],Citation[59], promotes adhesion, migration, and invasion of trophoblast cell Citation[131],Citation[132], has an inhibitory effect on early hematopoietic progenitors Citation[133], and regulates intestinal crypt cell renewal in both physiologic conditions and during mucosal regeneration following injury Citation[134].

The biological properties of IP-10 are mediated through the interaction with a transmembrane G protein-coupled receptor, CXCR3 Citation[135],Citation[136] shared by two other IFN-γ inducible CXC chemokines—CXCL9 (MIG) and CXCL11 (I-TAC)—whose distinct biological activities are related to different transduction pathways Citation[137-140].

Factors controlling the expression of IP-10 and cell sources

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[61], neutrophils Citation[69],Citation[70], eosinophils Citation[70],Citation[141], keratinocytes Citation[61],Citation[64],Citation[65],Citation[67], fibroblasts Citation[61], endothelial cells Citation[61-63], pancreatic β cells Citation[71],Citation[72], and animal astrocytes/microglia Citation[66],Citation[68], TNF-αCitation[70],Citation[73-79], interleukin (IL)-1βCitation[70],Citation[71], as well as viral Citation[66],Citation[81],Citation[82] and microbial products Citation[70],Citation[80],Citation[83-85], can also stimulate the production of IL-10.

Activation of the nuclear factor-kappa B (NF-kB) pathway Citation[81],Citation[82],Citation[86-89] through ligation of pattern recognition receptors (TLR4 Citation[83] and TLR3 Citation[89]) can also upregulate gene and protein expression of IP-10. Interestingly, IP-10 is considered an ‘NF-kB responsive gene’Citation[142].

IP-10 in inflammation

The pro-inflammatory activity of IP-10 includes: chemotaxis and endothelial adhesion of activated T cells Citation[143] as well as chemotaxis Citation[144] and enhancement of natural killer (NK) cell-mediated cytolysis Citation[144]. However, this chemokine is a poor neutrophil activator Citation[143],Citation[145] and there is controversy about its effects on both monocytes Citation[135],Citation[143] and B cells Citation[146],Citation[147].

CXCR3 receptor expression on T lymphocytes is selective for activated cells Citation[135],Citation[143],Citation[146],Citation[148-151]. Interestingly, analysis of polarized T lymphocytes using specific monoclonal antibodies has demonstrated high CXCR3 expression (mRNA and protein) on Th1 cells and low on Th2 cells Citation[149],Citation[152], and this receptor has, therefore, been proposed as a useful clinical marker of circulating Th1-type cells Citation[149],Citation[153]. Further evidence that IP-10 promotes a Th1-like dominance is the observation that, following stimulation with phorbol-12-myristate 13-acetate (PMA) and ionomycin, the production of IFN-γ (a Th1-type chemokine) resides exclusively in CXCR3-expressing memory CD4+ T cells, whereas the production of Th2-type cytokines is mainly observed in those CXCR3-negative Citation[153]. In addition, in vitro assays show that, in polyclonally stimulated T cells, recombinant IP-10 selectively enhances IFN-γ protein synthesis, while having no effect on IL-4 production Citation[154]. The capability of IP-10 to enhance its own inducer, IFN-γ supports the hypothesis that a positive amplification loop between IP-10 and IFN-γ also exists in vivoCitation[154].

IP-10 in pathologic states

IP-10 has been implicated in states characterized by a prominent T cell response Citation[155],Citation[156], particularly when a Th1/Th2 imbalance is involved, including: (1) multiple sclerosis, where the serum and cerebrospinal fluid concentrations of IP10 correlate with the disease activity and CXCR3 expression is detectable on the majority of CNS-infiltrating lymphocytes Citation[104-108]; (2) herpetic encephalitis in mice Citation[157],Citation[158]; (3) experimental autoimmune encephalomyelitis Citation[159-162]; (4) inflammatory bowel/colon disease Citation[134],Citation[163],Citation[164]; (5) chronic hepatitis C, in which IP-10 serum concentrations are related to the inflammatory activity and the response to therapy Citation[165]; (6) Sjogren's syndrome, where the expression of IP-10 mRNA is significantly up-regulated in salivary glands (p < 0.01) and IP-10 has a potential role in the accumulation of T cells infiltrates Citation[166]; (7) type 1 diabetes, whose immunopathogenesis is likely to be linked to the IP-10 Citation[109],Citation[110] property of enhancing the traffic of auto-aggressive cells to the pancreas Citation[167] and imprinting a pattern for the subsequent development of the autoimmune disease Citation[109]; (8) Graves' disease Citation[111-114] and autoimmune thyroiditis Citation[115],Citation[116] where high concentrations of IP-10 have been detected in the serum of affected individuals; and (9) systemic lupus erythematosus, where IP-10 plasma concentrations not only are higher than in non-diseased individuals but also correlate with the disease activity Citation[168].

IP-10 as an inhibitor of angiogenesis

IP-10 has potent anti-angiogenic properties Citation[54],Citation[56],Citation[57],Citation[59]. Several mechanisms have been proposed to mediate these activities: (1) interaction with the CXCR3 receptor Citation[169],Citation[170]; (2) binding to a cell surface heparan sulfate site shared with platelet factor 4 Citation[124]; (3) interference with the pro-angiogenic activity of basic fibroblast growth factor (bFGF) and IL-8 Citation[124]; and (4) through another high affinity receptor (different from CXCR3 and glycosaminoglycans) Citation[171].

The IP-10 receptor CXCR3 (mRNA and protein) has been localized on the endothelial cells of several human tissues (kidney, gut, liver, thyroid, and thymus) Citation[170],Citation[172]. Interestingly, the endothelial cell expression is cell cycle-dependent Citation[170]. Indeed, staining is remarkably more frequent in conditions of activation and in the presence of a high proliferative rate (such as in inflamed and neoplastic tissues rather than in normal tissues), particularly during the S/G2-M phase of the endothelial cell cycle Citation[170]. Romagnani et al. Citation[170] suggested that these results represent evidence that CXCR3 is mediating the angiostatic activity of IP-10, thus controlling endothelial cell proliferation. In addition, two distinct isoforms of this receptor, CXCR3-A and CXCR3-B (both products of alternative splicing) are likely to mediate opposite effects on cellular proliferation Citation[173],Citation[174].

A specific region of the IP-10 molecule has been linked to its anti-angiogenic effect. Indeed, an aminoterminal truncated form of IP-10, resulting from a post-translational processing, has impaired receptor signaling and lymphocyte chemotaxis, but retains anti-angiogenic properties Citation[175].

Evidence in support of the anti-angiogenic role of IP-10 includes: (1) IP-10, added to human umbilical cord vein endothelial cells (HUVECs), cultured on a matrigel substrate, inhibits their differentiation into tube-like structures in a dose-dependent fashion Citation[125] and reduces the extent of the neo-vascular network Citation[126]; (2) IP-10, both in vitroCitation[123],Citation[124] and in vivoCitation[123],Citation[125] inhibits in a dose-dependent manner the pro-angiogenic effects of IL-8 and bFGF, including endothelial cell chemotaxis and proliferation as well as neovascularization in animal models of angiogenesis (rat cornea Citation[123] or matrigel injected in the subcutaneous tissue of nude mice Citation[125]); (3) recombinant IP-10 can inhibit [3H]-thymidine incorporation into HUVECs cultured with bFGF Citation[124]. Further support of the anti-angiogenic properties of IP-10 is the role attributed to this chemokine in the pathogenesis of pulmonary fibrosis. Indeed, the lower production of IP-10 in lung tissue of patients with pulmonary fibrosis, as determined by ELISA, has been proposed to contribute to the greater angiogenic activity observed in these patients Citation[117],Citation[119]. Additionally, when IP-10 is administered systemically to bleomycin pre-treated mice, it inhibits fibroplasia and deposition of extracellular matrix through the regulation of the local angiogenesis, resulting in a significant attenuation of the severity of the pulmonary fibrosis induced by this chemical Citation[118]. This experimental evidence indicates that IP-10 has an important anti-angiogenic effect.

Evidence that the anti-angiogenic properties of IP-10 may have therapeutic value is the observation that it inhibits tumor growth. Observations in support of this include: (1) Burkitt's tumors implanted into athymic mice, once injected or transfected with IP-10, show histological evidence of tissue necrosis, capillary damage, intimal thickening, and vascular thrombosis Citation[176]; (2) high serum concentrations of IP-10 have been reported in patients with lymphoproliferative disorders Citation[177]; (3) tumors derived from IP-10 transduced melanoma cells have a reduced in vivo growth compared to those originating from parental or null-transduced cells (p = 0.0002) and the growth inhibition is associated with a marked reduction in microvessel density Citation[178]; (4) the angiostatic activity of IP-10 in human melanoma cell line appears to depend on binding to CXCR3 Citation[169]; (5) tumors originating from human fibrosarcoma cell lines, secreting IP-10 upon vector transduction, and implanted into mice, have histological evidence of a significantly lower number of microvessels than controls (p = 0.01) Citation[126]; (6) recombinant IP-10 injection into non-small cell lung cancers grown in SCID (severe combined immunodeficiency) mice reduces their angiogenesis, growth, and incidence of spontaneous metastasis, whilst IP-10 neutralization results in enhanced tumor-derived angiogenic activity. Furthermore, plasma or tumor-associated IP-10 concentrations are inversely correlated to tumor growth. Extracts from these tumors decrease the angiogenic activity in the corneal micropocket assay Citation[179]; and (7) IP-10 contributes to the anti-angiogenic and anti-tumor properties of IL-12 Citation[180-183].

In summary, this evidence indicates that IP-10 plays an important anti-angiogenic role.

IP-10 concentration in serum during normal pregnancy

The observation that normal pregnant women have a significantly higher median serum concentration of IP-10 than non-pregnant women is novel. This observation is consistent with the findings that normal pregnancy is associated with systemic intravascular inflammation Citation[35],Citation[184-187]. Additional evidence in support of this view is the observation that pregnancy is associated with higher (serum or plasma) concentrations of IL-12 Citation[186] and TNF-αCitation[188] than the non-pregnant state.

IP-10, inflammation, and preeclampsia

The observation that preeclampsia is associated with a higher median maternal serum concentration of IP-10 than SGA and normal pregnancy is novel, as well as being consistent with the view that preeclampsia is characterized by an exaggerated intravascular pro-inflammatory state Citation[18],Citation[33-37].

Furthermore, accumulating evidence indicates that preeclampsia is associated with a predominant Th1 immune response, including: (1) high maternal plasma or serum concentrations of IL-2 Citation[38], TNF-αCitation[40],Citation[41],Citation[189-191], IFN-γCitation[192], and IL-12 Citation[42],Citation[193]; (2) low maternal plasma or serum concentrations of IL-10 Citation[194] and of IL-4 Citation[192] (although this topic is subject to some controversy) Citation[195]; and (3) up-regulation of mRNA and protein expression of IL-1βCitation[196] and TNF-αCitation[196],Citation[197] in the placenta. Thus, the high maternal plasma concentration of this chemokine in patients with preeclampsia may represent yet another feature of a pro-inflammatory state or intravascular inflammation or even contribute to the generation of such state. Some evidence also indicates that SGA may be associated with intravascular inflammation Citation[47]. However, the results presented herein do not implicate IP-10 in such process.

IP-10, preeclampsia, and anti-angiogenesis

An imbalance between pro-angiogenic and anti-angiogenic factors is involved in the pathophysiology of preeclampsia Citation[25-27],Citation[198-218]. The group of Maynard and Karumanchi has recently made a major set of observations that favors this hypothesis Citation[219]. Evidence in support of this includes: (1) over-expression of sVEGFR-1 mRNA and protein in placenta of patients with preeclampsia Citation[27],Citation[219]; (2) higher median plasma/serum concentration of sVEGFR-1 in preeclampsia at the time of diagnosis than in patients with normal pregnancies Citation[27],Citation[219],Citation[220] and the plasma concentration correlates with the severity of the disease Citation[28]; (3) preeclampsia is associated with decreased plasma/serum concentrations of VEGF and PlGF Citation[25],Citation[211],Citation[219],Citation[221]; (4) serum of pregnant women with preeclampsia has anti-angiogenic effects in the endothelial cell tube formation bioassay and these effects can be restored by the addition of VEGF and PlGF Citation[219]; and (5) administration of sVEGFR-1 to pregnant animals can induce the clinical manifestation of preeclampsia, including hypertension and proteinuria Citation[219]. Moreover, these animals develop the pathologic finding of glomerular endotheliosis but not pathognomonic of preeclampsia Citation[222],Citation[223]; and (6) preeclampsia is associated with a higher maternal serum concentration of endoglin at the time of the diagnosis or before the recognition of the disease Citation[31],Citation[32].

Given the evidence that IP-10 has anti-angiogenic properties and that this is a feature of preeclampsia, we propose that elevated IP-10 maternal serum concentrations may contribute to generating an anti-angiogenic state along with sVEGFR-1 and endoglin.

IP-10, preeclampsia, and allograft rejection

Allograft rejection has also been proposed as a mechanism of disease in preeclampsia Citation[224]. Of note, there is growing evidence that IP-10 is also involved in the process of graft rejection, including: (1) CXCR3 deficient (−/−) mice are resistant to both acute and chronic allograft rejection Citation[91]; (2) grafts from IP-10 (−/−) donors are less likely to undergo graft injury Citation[90]; (3) treatment with anti-CXCR3 Citation[91] or anti-CXCL10 Citation[96] monoclonal antibodies results in prolongation of cardiac and small bowel allograft survival in mice; (4) clinical rejection of human renal Citation[92],Citation[100], lung Citation[93], cardiac Citation[94],Citation[95], small bowel Citation[99], and arteries Citation[102] transplants is associated with intra-graft over expression of IP-10 and/or with intra-graft recruitment of CXCR3 positive T cells; and (5) pre-transplant serum Citation[97],Citation[103] and urine Citation[98],Citation[101] CXCL10 cellular mRNA or protein concentrations identify patients at risk for the development of acute rejection and/or chronic allograft nephropathy. Collectively, this evidence indicates that IP-10 is involved in the pathogenesis of allograft rejection. Whether or not this mechanism of disease operates in preeclampsia remains an interesting concept. Our observation that IP-10 is elevated in preeclampsia provides a possible link between preeclampsia and this potential pathologic process.

IP-10, preeclampsia, and atherosclerosis

Striking parallels exist between preeclampsia and atherosclerosis (see bibliography for details). Patients who develop preterm preeclampsia are at increased risk of death from coronary artery disease later in life Citation[225]. Moreover, atherosis of the spiral arteries, a lesion observed in patients with preeclampsia, has striking similarities with that of coronary artery disease Citation[226-228].

The current view of atherosclerosis is that it is an inflammatory mediated process Citation[229-231]. Th1 biased responses are thought to be pro-atherogenic, while Th2 biased immunoresponses confer atheroprotection Citation[232]. Chemokine-dependent migration of cells through the inflamed endothelium into the arterial intima has been proposed to be critical in atherosclerosis Citation[233-237]. There is evidence of a specific involvement of IP-10 in the pathogenesis of atherosclerosis and cardiovascular diseases. Such evidence includes: (1) patients with stable angiographically confirmed coronary heart disease have a higher mean IP-10 serum concentration than control patients, and the magnitude of the elevation correlates with the concentration of several acute-phase proteins (C-reactive proteins) or cytokines known to be central in the pathogenesis of atherosclerosis Citation[122]; (2) serum IP-10 baseline concentrations are significantly higher in individuals who develop coronary heart disease (CHD) than in those who do not (follow-up of 11 years). After adjustment for cardiovascular and immunological risk factors, however, the observed relationship with IP-10 disappeared, suggesting that the association may be explained by other markers of inflammation and not be specific to IP-10. Nonetheless, this observation is important because it suggests that an elevation of IP-10 precedes the development of CHD, thus strengthening the case that inflammation has a causal role rather being a consequence of atherosclerosis Citation[121]; (3) CXCR3-bearing T cells and chemokines IP-10, I-TAC, and MIG (all three IFN-γ-induced) are present in atherosclerotic plaques Citation[120].

Conclusions

Preeclampsia is associated with higher maternal plasma concentrations of IP-10 than normal pregnancy and SGA. These results suggest that this chemokine may contribute to both the exaggerated systemic inflammation and the anti-angiogenic state that characterize preeclampsia.

Acknowledgement

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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