Inflammation is an integral part of the body defense mechanism that occurs in vascularized tissue in response to harmful stimuli that is perceived as being a threat to tissue homeostasis. It is a complex physiological host response that is designed to neutralize and eliminate harmful agents, initiate tissue healing, and orchestrate a return to tissue homeostasis. While inflammation is designed to be an acute event that resolves following the elimination of harmful stimuli and tissue healing, there are instances where inflammation fails to resolve and instead evolves into chronic inflammation. It is now well understood that ongoing inflammation can serve as the underlying cause of many chronic inflammatory diseases, including atherosclerosis. In fact, one of the most pressing issues that is currently faced in the field of inflammation research, one that has also become the focus of numerous ongoing investigations, is how to turn this excessive, unwarranted and undesirable inflammation response off. Once thought to be a passive and simple process, resolution is now understood to be an active and complex process that is orchestrated by various inflammatory mediators, signaling pathways and biophysical processes. The discovery of novel biosynthetic pathways that turn on the pro-resolution signals has lead to a surge in research aimed at taking a closer look at processes that can stimulate the resolution of inflammation. While major advances in the field have resulted in a better understanding of the proactive nature of resolution, many of the mechanisms involved are still unknown. To date, the repertoire of chemokine receptors that participate in macrophage clearance during resolution, for the most part, remain unidentified. Overall, there is a growing appreciation that the discovery of mechanisms involved in the resolution responses can lead to the development of novel therapeutic approaches to resolve many chronic inflammatory diseases. Syndecan-1 (Sdc-1), a member of a family of cell surface proteoglycans, has been previously shown to regulate events relevant to tissue repair and chronic injury responses. Macrophage Sdc-1 expression during inflammation has been reported to be protective in various inflammatory models. Given these observations, we hypothesize that Sdc-1 expression on macrophages is a critical component of an anti-inflammatory, pro resolution program necessary for the successful resolution of inflammatory response. In this dissertation, we report the presence of a unique population of macrophages expressing Sdc-1 that are present within the vascular wall of mice undergoing atherosclerosis. Consistent with previous publications, the presence of Sdc-1 expressing macrophages was found to limit atherosclerosis progression. In addition, Sdc-1 expression on macrophages was associated with anti-inflammatory M2 polarization state and high intrinsic motility. Macrophage Sdc-1 expression was also linked with efferocytosis and enhanced macrophage egress from the site of inflammation to the draining lymphatic network. Moreover, we discovered that the chemokine receptor CXCR4, which was found on Sdc-1 expressing macrophages, was also involved in macrophage egress during inflammation resolution. In summary, while the overall mechanism regulating resolution processes is still unknown, our work has managed to identify two components that are involved in the process: macrophage Sdc-1 and CXCR4. Collectively, these results reinforce the physiological significance of macrophage efferocytosis and macrophage motility as endogenous modulators of the inflammatory response.

Bis heute sind über 50 Chemokine und fast 20 Chemokinrezeptoren identifiziert. Dennoch gibt es Chemokine und Chemokinrezeptoren, deren zugehörige Rezeptoren bzw. Liganden noch nicht bekannt sind. PARC (=CCL18) ist ein ausschließlich in Primaten nachgewiesenes, bisher nur wenig charakterisiertes, im Organismus jedoch weit verbreitetes Chemokin, für das bisher noch kein Rezeptor beschrieben wurde. Die Wirkung dieses Chemokins wurde bisher vor allem an T Lymphozyten nachgewiesen. Die vorliegende Arbeit untersucht die Wirkung von PARC auf B-Lymphozyten und das Vorkommen des putativen PARC-Rezeptors DRY12. Dabei wurden B-Zellen von CLL Patienten sowie mehrere standardisierte B-Zelllinien als Untersuchungsgut verwendet. In funktionellen Assays (Kalziummobilisation, Aktinpolymerisation und Chemotaxis) wurde die Wirkung von PARC auf diese Zellen charakterisiert. Untersuchungen zu beteiligten Signalkaskaden wurden durch Einsatz von spezifischen Inhibitoren (Pertussis-Toxin) und mittels Western Blot durchgeführt. Weiterhin wurde das Vorkommen des putativen PARC-Rezeptors DRY12 bei den verschiedenen B Lymphozyten mittels Antikörperfärbung und RT-PCR sowohl auf Protein- als auch auf mRNA-Ebene nachgewiesen. Der Nachweis der genauen Lokalisation des Rezeptors in der Zelle erfolgte mittels Immunfluoreszenzcytologie. Abschließend wurde vergleichend das Vorkommen des DRY12 im Lymphknoten von CLL-Patienten und gesunden Spendern untersucht. PARC löst bei den B-Zellen der CLL-Patienten die Polymerisation von Aktin aus. Es induziert jedoch keine gerichtete Migration der Zellen. PARC wirkt auf die in dieser Arbeit untersuchten B-Zellen also nicht als Chemokin im klassischen Sinne. Seine Wirkung besteht möglicherweise in einem synergistischen Effekt, indem es im Zusammenspiel mit anderen Faktoren die Migration der Zellen beeinflusst. Weiterhin wäre denkbar, dass PARC das Verhalten von hämatopoetischen Stamm- und Vorläuferzellen beeinflusst. Die beteiligte Signalkaskade beinhaltet ein Pertussis-Toxin-sensitives Gi-Protein und die Aktivierung der p42/44-MAP Kinase. Ein intrazellulärer Einstrom von Ca2+ spielt bei der Wirkungsvermittlung von PARC keine Rolle. Der putative PARC-Rezeptor DRY12 konnte bei verschiedenen B-Zellen in unterschiedlicher Intensität nachgewiesen werden. Die Expression des DRY12 scheint sowohl auf Ebene der mRNA als auch auf Proteinebene durch multiple Faktoren reguliert zu sein. Dazu gehören z.B. der Reifungs- und Aktivierungszustand der Zellen oder die Kultivierungsdauer nach dem Auftauen der Zellen bis zur Durchführung des Versuchs. Bisher konnten jedoch keine entsprechenden Zusammenhänge nachgewiesen werden. Der DRY12 ist demnach kein konstitutiv exprimierter Rezeptor. Durch Immunfluoreszenzcytologie konnte die Lokalisation des Rezeptormoleküls auf der Zelloberfläche gezeigt werden. Im Lymphknoten wird DRY12 v.a. von Lymphozyten exprimiert. Bei Makrophagen konnte das Rezeptorprotein nicht nachgewiesen werden. In den Lymphknoten von CLL-Patienten exprimieren die Lymphozyten deutlich mehr DRY12 als Lymphozyten im Gewebe gesunder Individuen. Ein direkter Zusammenhang zwischen Rezeptorexpression und Reaktion auf PARC konnte nicht sicher aufgezeigt werden. Die Ergebnisse dieser Arbeit schließen aber auch nicht aus, dass PARC ein möglicher Bindungspartner von DRY12 ist. Bei der Wirkungsvermittlung spielen vermutlich auch andere Botenstoffe und weitere Faktoren eine Rolle, indem sie die Reaktionsfähigkeit der Zellen gegenüber PARC bzw. die Rezeptorexpression des DRY12 beeinflussen. Hinsichtlich der Frage, ob es sich bei DRY12 um einen Rezeptor für PARC handelt, kann diese Untersuchung zu keinem abschließenden Ergebnis gelangen, so dass dieser Aspekt in weiterführenden Analysen eingehender betrachtet werden sollte. / Today there are more than 50 chemokines and almost 20 chemokine receptors described. Despite growing knowledge, the ligands for some orphan chemokine receptors have not been identified and for several chemokines the receptor has not been discovered. PARC (=CCL18) is one of these chemokines for which the receptor has not been recognized. It has been detected in primates only and, despite being widely spread in the organism, it is still poorly characterized. Up to now, the effects of PARC were mainly shown on T-lymphocytes. Therefore, the objective of this study was to investigate the function of PARC and the expression of the putative PARC-receptor DRY12 in B-lymphocytes. For the purpose of the present study, B-CLL-cells and several lymphocytic B-cell-lines served as models to cover different stages of B-cell maturation. In order to characterize the effect of PARC, several functional assays (calciummobilisation, actinpolymerisation and chemotaxis), specific inhibitors (pertussis toxin) and Western Blotting were used. Expression analyses of the DRY12-receptor were performed by FACS-analysis, RT-PCR and immunofluorescence cytochemistry. In addition, lymph nodes from patients with CLL and healthy donors were stained immunohistochemically. In B-CLL-cells, PARC stimulation leads to phosphorylation of p42/44-MAP-Kinase and polymerization of actin, which can be inhibited by pertussis toxin, but does not induce calcium signaling or chemotactic migration. In this case, PARC is no classical chemokine but may act as synergist to potentiate the effect of other chemokines or may influence the behavior of hematopoetic stemm-cells. The results of the study show expression of the putative PARC-receptor DRY12 present on several subsets of B lymphocytes. As they showed different intensity of expression, DRY12 may be regulated by different factors in translation as well as transduction. Among these factors might be their current state of maturation and activation and the time period from revitalization to the start of the experiments. The reasons for these differences are still unknown. According to these findings, the receptor is not constitutively expressed, but may be itself regulated by several chemokines and other factors. DRY12 is located at the surface of the cell, as shown by immunocytochemistry. In lymph nodes, particularly lymphocytes but not macrophages express DRY12. In lymph nodes of CLL-patients lymphocytes express much more DRY12 than in healthy samples. However, it could not be proved that DRY12 is the agonistic receptor for PARC, as the expression of DRY12 did not completely correlate with the effects on PARC stimulation. But results of this study do not exclude this possibility either, as different factors are considered to influence the effect of PARC and the expression of DRY12 in B-cells. Although there are hints to it, from this study we can not conclude that DRY12 is the agonistic receptor for PARC. Therefore, further investigation is necessary to find the answer to this question.

Abstract Early in the evolution of the vertebrates it is thought that two genomic duplications occurred, providing a basis for the evolution in body plan and neural crest of very early vertebrates and substantive material for further evolution of various gene families such as those making up a number of components of the adaptive vertebrate immune system. While the bony fish possibly had another, genome duplications are not generally a feature of vertebrate evolution and indeed the appearance of an antigen-adaptive immune recognition system may have served to limit the size that various vertebrate genomes, including that of the human, can in fact achieve. This initial step in vertebrate immune evolution, the establishment of recognition of non-self against the unique set of 'self' epitopes for an individual, provided an immensely powerful weapon in immune function with the ability to tailor a defense against as-yet-unseen dangers at any time albeit with the pitfall of autoimmune disease. As the recognition sites of the antigen receptor molecules such as TcR are produced by clonal modification of the segments provided in the germline and are thus not in the genome itself, pathogens have not been able to hijack this one component of the immune system in the way so many other components have been put to use throughout evolution, nor do these components necessarily reveal themselves as associated with disease through genome screens. Importantly, overall immune function is determined not just by the potential repertoire of recognition receptors but also by the ability of immunocompetent cells to migrate in a tissue specific fashion through the use of various chemokines and their receptors. Typical of the hijacking of an immune system component by a pathogen is the use of a chemokine ligand gene in the viral ancestor to SIV and HIV, allowing for virus binding to immunocompetent cells as is seen in the use of the CCR5 chemokine receptor by macrophage-tropic HIV strains. This thesis describes the allele and genotype frequencies for several TcR beta-chain variable segment polymorphisms in a population of MS patients compared with controls before and after stratification for HLA-DR15, polymorphism in the Apo-1 / Fas promoter, the DRB1 Val86/Val86 genotype, CCR5-delta32 and the HLA-DRA promoter. The thesis continues with CCR5-delta32 genotyping in IDDM, MS and SLE cohorts and then examines the question of the population of origin of the delta-32 allele of the CCR5 receptor for chemokine. Here, a case / control comparison of 122 RR-MS patients with 96 normal individuals was made for allele and genotype frequencies and for haplotypes formed by pairs of TCRB markers. Further analysis was made after HLA-DR15 stratification. Linkage disequilibrium was found between pairs of alleles of bv8s1, bv10s1, bv15s1 and bv3s1 loci in both patients and controls. In the RR-MS cohort, an increase in the allele frequency of bv8s1*2 was seen (p = 0.03) and the haplotype bv8s1*2 / bv3s1*1 was increased (p = 0.006), and both were found to be statistically significant. In the DR15-positive group, association between MS and TCRB was seen with the bv8s1*2 allele (p = 0.05) and the bv8s1*2 / bv10s1 haplotypes (p = 0.048), while the haplotype associations seen among the DR15-negative patients included the bv3s1*1 allele (bv10s1*1 / bv3s1*1, p = 0.022; bv8s1*2 / bv3s1*1, p = 0.048). While no associations were found after stratification for SDF1-3'A, Apo-1 / Fas or DRB1 there were modest interactions between bv3s1, bv10s1 and bv15s1 and the HLA-DRA promoter. These results support the involvement of the TCRB region in MS susceptibility. The further study of autoimmune disease here includes genotype analysis of CCR5-delta32 in type 1 diabetes (IDDM) and SLE. CCR5 is the major co-receptor for viral entry used by macrophage-tropic HIV strains and protection from infection is seen in homozygotes for CCR5-delta32. In diabetes, infiltration of pancreatic tissue by autoreactive T-cells involves secretion of multiple cytokines and chemokine receptor expression. Variation in the chemokine receptor CCR5 may result in differences in inflammatory cell migration in response to relevant chemokines. Adolescents with type 1 diabetes were genotyped for CCR5-delta32 (n = 626). The allele frequency was compared with that of 253 non-diabetic adolescents and with that of 92 adults with SLE. A reduced allele frequency was seen in type 1 diabetes compared with controls (0.092 vs 0.123, p = 0.05). This difference was not seen for the cohort of patients with SLE (freq = 0.114). A reduction in the number of CCR5-delta32/delta32 homozygotes, who lack CCR5, in the type 1 diabetes cohort was also seen and while not statistically significant (2 observed compared to 5.25 expected; p = 0.12) is interesting. These results suggest a partial protection from type 1 diabetes for CCR5-delta32 homozygous individuals is possible and that CCR5 has a potential role in the pathogenesis of type 1 diabetes. Global surveys of the CCR5-delta32 allele have confirmed a single mutation event in a Northeastern European population as the source of this allele. Here, Australian Ashkenazi Jews (n = 807) were found to have a CCR5-delta32 allele frequency of 14.6% while Australian Sephardic Jews (n = 35) had a frequency of 5.7% and non-Jewish Australian controls (n = 311) had an allele frequency of 11.25%. Data on birthplace of grandparents showed a gradient with highest CCR5-delta32 frequencies from Eastern European Ashkenazim (~19.5% for those whose four grandparents come only from Russia, Poland, Hungary, Austria and Czechoslovakia; n = 197) which differs significantly from the frequency seen in Ashkenazi Jews from Western Europe (n = 101, p = 0.001). Homozygotes for CCR5-delta32 were genotyped with 3p21 region microsatellites. This has defined an ancestral haplotype on which the mutation first occurred and helped to date this event to between 40 and 50 generations ago or just over a thousand years ago. The population gradient, combined with the dating of the mutation by microsatellite allele frequencies, suggests an origin for the CCR5-delta32 allele in a population ancestral to the Ashkenazim. The distribution in non-Jewish populations in northern Europe has led others to postulate spread of the mutation by Vikings. It is hypothesised here that the link between the two populations could be the kingdom of Khazaria with subsequent admixture into both Swedish Vikings and Ashkenazi Jews. The basic driving force of evolution is through selection and the immune system has a role which, through the survival pressure exerted by viruses and other pathogens, has the potential to exert a great deal of selective force on the various components of this system. The effects of this pronounced selection on an immune system component can be seen for example in the increase of the CCR5-delta32 allele over the last thousand years to the current frequency. As mentioned, some immune system components are not affected by such straightforward selection. In the case of the TCRBV segments, effects on the immune repertoire can occur through MHC interaction at the point of thymic entry and in the effects of various superantigens, but the actual binding pockets that recognise antigen are themselves unable to be selected for (or against). The findings presented in this thesis provide support for the association of TCRBV gene segments with multiple sclerosis and also provide support for the further study of the role of the CCR5-delta32 allele in type 1 diabetes. Furthermore, data presented here suggests that the CCR5-delta32 allele had an origin in the Khazar Kingdom just over a thousand years ago, accounting for the allele frequencies in both the Ashkenazi Jews and in lands frequented by the Vikings. The definition of an extended ancestral haplotype for the CCR5-delta32 allele shows how the effect of selection of an allele of one gene can carry with it specific alleles of a large number of other genes as well.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (Ph.D.). / Written for the Dept. of Medicine, Division of Experimental Medicine. Title from title page of PDF (viewed 2009/06/09). Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (leaves 71-91).

A successful immune response depends on prompt and sufficient recruitment of leukocytes from the circulation to infected or injured sites. Mobilization of leukocytes to hypoxic tissues is vital for angiogenesis, i.e. the formation of new blood vessels from preexisting vasculature, and thus crucial for tissue growth and regeneration. Deviations from normal leukocyte recruitment drive a variety of pathologies, including chronic inflammation, autoimmune diseases and cancer, for which therapeutic options are limited or unspecific. Understanding the mechanisms by which the body controls leukocyte recruitment is therefore critical for the development of novel therapeutic strategies. The present investigations focused on delineating the mechanisms behind leukocyte mobilization from the bloodstream to afflicted sites, by means of in vivo imaging techniques and in vitro assays. We demonstrate that, in response to inflammation, increased vascular permeability enhances transendothelial transport of tissue-released chemokines. Within the vasculature, chemokines form a chemotactic gradient sequestered on heparan sulfate, which directs crawling neutrophils and expedites their extravasation to the inflamed tissue. Consequently, gradient formation grants efficient bacterial clearance. Citrullination of chemokines by leukocyte-derived PAD enzymes in the inflamed tissue prevents chemokine transport into blood vessels, which dampens further neutrophil recruitment and thereby controls the amplitude of the inflammatory response. Moreover, the mechanisms of neutrophil recruitment in response to proangiogenic factors released during hypoxia are revealed to differ from those observed during classical inflammation. Particularly, VLA-4 integrin and VEGFR1 expressed on a defined subset of neutrophils, along with endothelial VEGFR2, are required for efficient neutrophil recruitment to hypoxia. Rather than stimulus-induced phenotypic changes on neutrophils, specific neutrophil subtypes with innate proinflammatory or proangiogenic functions (respectively, CD49d-VEGFR1lowCXCR4low and CD49d+VEGFR1highCXCR4high) coexist in the circulation of humans and mice. In summary, this dissertation provides relevant information on specific steps of neutrophil recruitment to inflamed or hypoxic tissues, which may represent future means to down-regulate aberrant immune responses during chronic inflammation and autoimmune diseases; to increase angiogenesis during ischemia; or to limit pathological angiogenesis, a characteristic of tumor growth and of several chronic inflammatory disorders.

Avec 42 000 nouveaux cas diagnostiqués en 2012, le cancer colorectal (CCR) représente en France le troisième cancer en termes d’incidence. Les métastases, qui surviennent principalement au niveau du foie et des poumons, en constituent la principale cause de décès. Malgré les progrès récents de la chimiothérapie et des agents ciblés, le taux de survie à 5 ans des patients présentant un CCR métastasé reste faible. Aujourd’hui, la résection chirurgicale est le seul traitement curatif, cependant moins de 20% des patients porteurs de métastases sont opérables. Il existe donc un grand nombre de patients présentant un CCR métastasé pour lequel aucun traitement curatif ne peut être proposé. La formation des métastases à partir d’une tumeur primaire résulte d’une longue série d’étapes séquentielles liées les unes aux autres. L’issue de ce processus dépend à la fois des propriétés intrinsèques des cellules tumorales et de la réponse de l’hôte. Il a récemment été montré que les couples chimiokines/récepteurs interviennent dans le contrôle des différentes étapes de la progression tumorale.Le projet de recherche développé au cours de mon travail de thèse avait pour objectif d’utiliser les chimiokines et leurs récepteurs dans de nouvelles stratégies thérapeutiques pour bloquer et/ou éradiquer les métastases hépatiques et pulmonaires des CCRs. Le travail s’est articulé selon deux axes dans lesquels nous avons montré d’une part que, le blocage du récepteur de chimiokines CXCR7 permet de limiter les métastases pulmonaires de CCRs et d’autre part que, le transfert de gène codant CX3CL1 au niveau du foie entraîne une réponse anti-tumorale efficace dans les métastases hépatiques de CCRs. / With 42 000 newly-diagnosed patients in 2012, the colorectal cancer (CRC) represents the third type of cancer in terms of incidence in France. The leading cause of death from CRC is the development of metastases and these metastases will occur mostly within the liver (50% of the patients) and within the lungs (15%). Despite recent progress, notably in the chemotherapies now used and the targeted agents, the rate of 5-years survival for late stage CRC remains low. Nowadays, the surgical resection is the only curative treatment proposed to patients with metastatic CRC, however less than 20% of them have an operable tumour. There is therefore a high number of patients for whom no cure is currently available. A primary tumour’s dissemination to a second organ is the result of a long process made of numerous cross-linked steps. The final outcome of this process depends on the intrinsic properties of tumour cells as well as the host response. Recently, it has been shown that the chemokine-chemokine receptor pairs (initially described as regulating the leukocyte migration) play crucial roles in the various stages involved in tumour progression. The aim of the research project developed during my PhD was to assess the use of the chemokines and their receptors in new therapeutic strategies to block and/or eradicate the hepatic and pulmonary metastases of CRC. Our work has been organized along two main lines of approach. We have shown that the blockage of the CXCR7 chemokine receptor enables the limitation of the CRC metastases within the lungs and that the CX3CL1 gene transfer into the hepatocytes leads to an efficient anti-tumor response in the CRC metastases within the liver.

A neutropenia é um achado freqüente em recém-nascidos de mães com pré-eclampsia. Estudos avaliando a ativação leucocitária nestes recém-nascidos são escassos. No entanto, as principais citocinas pró-inflamatórias envolvidas são a IL-8 e o GRO-α. O objetivo deste estudo foi avaliar os níveis plasmáticos de IL-8 e GRO-α em recémnascidos prematuros de mães com pré-eclampsia. Metodologia: Foram incluídos recém-nascidos com idade gestacional menor de 36 semanas e peso de nascimento inferior a 2000 gramas, sendo divididos em dois grupos de acordo com a presença ou ausência de pré-eclampsia materna. Os critérios de exclusão foram: malformações congênitas, erro inato de metabolismo ou anormalidades cromossômicas, infecções do grupo STORCH, óbito na sala de parto e recém-nascidos nos quais as mães possuíam hipertensão crônica sem a presença de pré-eclampsia. Nas primeiras 48 horas de vida, no momento de coleta assistencial, uma pequena amostra adicional de sangue foi obtida para dosagem de IL-8 e GRO-α pelo método de enzimoimunoensaio. Foram usados os testes qui-quadrado, T student, Mann-Whitney, Kruskal-Wallis e regressão logística múltipla. Resultados: 119 recém-prematuros (64 sem pré-eclampsia e 55 com pré-eclampsia). Os grupos foram similares quanto ao peso de nascimento, idade gestacional, escore de Apgar no 5’minuto, sepse, doença de membrana hialina , ventilação mecânica, nutrição parenteral total, enterocolite necrosante, hemorragia periventricular. O grupo com préeclampsia apresentou mais neutropenia, foi mais PIG, parto cesariano e menos bolsa rota superior a 18 horas. Os níveis de IL-8 foram maiores no grupo sem pré-eclampsia materna [157.1 pg/ml (86.4-261.3) e 26.54 pg/ml (3.6-87.2) p<0.001 para não préeclampticos e pré-eclampticos, respectivamente]. Após análise por regressão múltipla apenas a ausência de pré-eclampsia foi associada com níveis elevados de IL-8. Conclusão: O prematuro de mãe com pré-eclampsia apresenta níveis reduzidos de IL-8, sugerindo que a ativação leucocitária possa estar prejudicada nestes recém-nascidos. / Neutropenia is frequent in newborn infants of preeclamptic mothers.Information on leukocyte activation in those newborns is scarce, but IL-8 and GRO- are the main proinflammatory cytokines involved. The aim was to study IL-8 and GRO- plasma levels in preterm newborn infants of preeclamptic mothers. Methods: Newborn infants with gestational age < 36 weeks and birth weight < 2000 grams were included and divided: non-preeclamptic and preeclamptic groups. Exclusion criteria: major congenital malformations, inborn errors of metabolism or chromosomal anomalies,STORCH infections, inborn preterm that died in the delivery room, and those whose mothers had chronic hypertension without preeclampsia. During the regular blood sample collection in the first 48 hours, a small amount was used for IL-8 and GRO- measurement by enzyme immunoassay. Chi-square, Student s t test, Mann Whitney test, Kruskal-Wallis and multiple logistic regression model were employed. Results: 119 preterm infants (64 non-preeclamptic and 55 preeclamptic). They were similar in birth weight, gestational age, Apgar scores at 5 minutes, sepsis, SDR, mechanical ventilation, TPN, NEC, intraventricular hemorrhage and death. The preeclamptic group had more neutropenia, SGA, C Section, and less rupture of membranes for > 18 hours. IL-8 was higher in the non-preeclamptic [157.1 pg/ml (86.4-261.3) e 26.54 pg/ml (3.6-87.2) p<0.001 non-preeclamptic and preeclamptic groups, respectively]. GRO-α was similar [229.5 pg/ml (116.6-321.3) and 185.5 pg/ml (63.9-306.7) p=0.236 in non-preeclamptic and preeclamptic groups, respectively]. After multiple regression analysis only absence of preeclampsia was associated with high IL-8 levels. Conclusions: Preterm newborn infants of preeclamptic mothers have a decreased plasma level of IL-8, suggesting that the leukocyte activation may be impaired in infants of preeclamptic mothers.