Evolution in heterogeneous populations: from migration models to fixation probabilities.

Although dispersal is recognized as a key issue in several fields of population biology (such as behavioral ecology, population genetics, metapopulation dynamics or evolutionary modeling), these disciplines focus on different aspects of the concept and often make different implicit assumptions regarding migration models. Using simulations, we investigate how such assumptions translate into effective gene flow and fixation probability of selected alleles. Assumptions regarding migration type (e.g. source-sink, resident pre-emption, or balanced dispersal) and patterns (e.g. stepping-stone versus island dispersal) have large impacts when demes differ in sizes or selective pressures. The effects of fragmentation, as well as the spatial localization of newly arising mutations, also strongly depend on migration type and patterns. Migration rate also matters: depending on the migration type, fixation probabilities at an intermediate migration rate may lie outside the range defined by the low- and high-migration limits when demes differ in sizes. Given the extreme sensitivity of fixation probability to characteristics of dispersal, we underline the importance of making explicit (and documenting empirically) the crucial ecological/ behavioral assumptions underlying migration models.

Migration across Spanish provinces: Evidence from the social security records (1978-1992)

This paper uses Social Security records to study internal migrationin Spain. This is the first paper that uses this data source, whichhas some advantages with respect to existing data sources: it includesonly job-seeking migrants and it allows to identify temporary migration. Within the framework of an extended gravity model, we estimate a Generalized Negative Binomial regression on gross migration flows between provinces. We quantify the effect of local labor market imbalances on workers' mobility and discuss the equilibrating role of internal migration in Spain. Our main results show that the effect of employment opportunities have changed after 1984; migrants seem to be more responsive to economic conditions but, consistently with previous studies for the Spanish labor market, the migration response to wage differentials is wrongly signed. Our analysis also confirms the larger internal mobility of highly qualified workers.

ARE PPARS NOVEL THERAPEUTIC TARGETS TO IMPROVE MELANOMA TREATMENT ?

Cutaneous melanoma is an aggressive malignant tumor of melanocytes, the pigment- producing cells of the epidermis, with a high incidence in developed countries. Despite some major clinical breakthroughs in the last few years, efficient therapies for metastatic melanoma, which portends a very bad prognosis, are still lacking. Among the potential therapeutic targets that have been attracting at-tention in melanoma are the peroxisome proliferator-activated receptors (PPARs). These members - a, ß and 7 - of the nuclear hormone receptor family, which are ligand-gated transcription factors endowed with a multitude of functions besides metabolism homeostasis, have displayed promising antitumor properties in a wide range of cancer cells, including melanoma. However, our knowledge of PPARs' functions in this skin cancer is far from complete, making the usefulness of any of the a, ß or 7 isotype as a therapeutic target uncertain. In this work, we showed that all three PPAR isotypes are expressed in normal melanocytes, in most melanoma cell lines and in primary and metastatic melanomas, and that PPAR/3 and 7 display transcriptional activity in normal melanocytes and melanoma cells. We also showed that the PPAR7 agonist rosiglitazone had anti-melanoma properties largely independent of PPAR7 expression, which was widely varying across the different cell lines and melanoma biopsies we evaluated and was not correlated with cell line stage. Consistent with the general view of PPAR7 as a tumor suppressor gene, we found that, in human samples, PPAR7 was less expressed in melanoma than in normal skin. Transcriptornic profiling of metastatic melanoma cells in which PPAR7 was pharmacologically modulated revealed an association with epithelial-to-mesenchymal transition, though the functional relevance of this finding remains to be determined. Collectively, our results suggests that PPAR7 activity in melanoma is highly complex and that a straightforward picture of PPAR7's role in this skin cancer is difficult to draw. In this study, we also provided compelling evidence that thioredoxin interacting protein (TXNIP) is, in melanoma, a bona fide PPAR7 target gene, the expression of which is repressed by PPAR7 activation. Although TXNIP is mostly known as an inhibitor of the major antioxidant thioredoxin, it has demonstrated a range of biological functions and is generally considered as a tumor suppressor gene. Consistently, we found that TXNIP expression is associated with growth arrest of melanoma cells in vitro and that forced expression of TXNIP strongly impairs cell proliferation. Interestingly, we also discovered that TXNIP favors melanoma cell migration while it diminishes their adhesion. Finally, we provided several lines of evidence that TXNIP may regulate these processes at the transcriptional level as well as by direct protein-protein interactions in the plasma membrane. Altogether, our findings suggest that the PPAR7 target TXNIP may be a double-edged sword in melanoma, hindering tumor growth but promoting invasion and dissemination. Experiments to evaluate the net biological outcome of TXNIP modulation in vivo are ongoing. -- Le mélanome cutané est une tumeur maligne agressive des mélanocytes, cellules de l'épiderme qui produisent la mélanine. Ce cancer présente un taux d'incidence élevé dans les pays développés et est grevé d'un pronostic très sombre une fois qu'il a disséminé. Malgré les importants progrès réalisés ces dernières années, aucune thérapie lie s'est encore montrée véritablement efficace contre le mélanome métastatique. Parmi les cibles thérapeutiques potentielles, nombre de groupes de recherche se sont penchés sur les peroxisome proliferator-activated receptors (PPARs). Ces récepteurs - a, ß et 7 - font partie de la famille des récepteurs nucléaires aux hormones, des facteurs de transcription activés par des ligands et dotés d'une multitude de fonctions en sus de la régulation du métabolisme. Ces protéines ont démontré des propriétés anti-tumorales prometteuses dans une large gamme de cellules cancéreuses, y compris le mélanome. Cependant, nous connaissons encore très mal les fonctions des PPARs dans ce cancer de la peau, rendant l'utilité thérapeutique de l'un des isotypes a, ß ou 7 incertaine. Dans ce travail, nous avons montré que les trois isotypes sont exprimés dans les mélanocytes normaux, dans la plupart des lignées de mélanome ainsi que dans des mélanomes primaires et métastatiques; nous avons aussi montré que PPAR/3 et 7 sont actifs sur le plan transcriptionnel dans les mélanocytes normaux et les cellules de mélanome. La rosiglitazone, un agoniste de PPAR7, a démontré des propriétés anti-mélanome essentiellement indépendantes de l'expression de PPAR7, qui semble très variable dans les lignées et les biopsies que nous avons évaluées; de plus, l'expression de PPAR7 n'est pas corrélée avec le stade de la lignée. En accord avec la vision communément admise de PPAR7 comme étant un gène suppresseur de tumeur, nous avons observé dans des échantillons humains que PPAR7 est moins exprimé dans les mélanomes que dans la peau normale. Une étude transcrip- tomique de cellules de mélanome métastatique a révélé que la modulation phar-macologique de PPAR7 est associée avec la transition épithélio-mésenchymateuse, même si la pertinence fonctionnelle de cette trouvaille reste à déterminer. Collec-tivement, ces résultats suggèrent que l'activité de PPAR/y dans le mélanome est hautement complexe et qu'une image claire du rôle de PPAR7 dans ce cancer est difficile à dessiner. Dans cette étude, nous avons également fourni de solides preuves que la thiore-doxin interacting protein (TXNIP) est, dans le mélanome, un gène cible bona fide de PPAR7 dont l'expression est réprimée par l'activation de PPAR7. Bien que TXNIP soit surtout connu comme un inhibiteur de la thiorédoxine -un anti-oxydant majeur - cette protéine a démontré une large gamme de fonctions biologiques et est généralement considérée comme un gène suppresseur de tumeur. En accord avec cette conception, nous avons trouvé que l'expression de TXNIP est associée avec l'arrêt de croissance des cellules de mélanome in vitro et que l'expression forcée de TXNIP freine considérablement la prolifération cellulaire. Nous avons aussi découvert que TXNIP favorise la migration des cellules de mélanome alors qu'elle diminue leur adhésion. Enfin, nous avons obtenu plusieurs preuves que TXNIP pourrait réguler ces processus tant au niveau transcriptionnel que par des interactions protéine-protéine au sein de la membrane plasmique. En conclusion, nos résultats suggèrent que la cible de PPAR7 TXNIP pourrait être une épée à double tranchant dans le mélanome, freinant la croissance tumorale mais favorisant l'invasion et la dissémination. Des expériences permettant d'évaluer l'effet biologique net de la modulation de TXNIP in vivo sont en cours.

The dexamethasone-induced inhibition of proliferation, migration, and invasion in glioma cell lines is antagonized by macrophage migration inhibitory factor (MIF) and can be enhanced by specific MIF inhibitors.

Glioblastomas (GBMs) are the most frequent and malignant brain tumors in adults. Glucocorticoids (GCs) are routinely used in the treatment of GBMs for their capacity to reduce the tumor-associated edema. Few in vitro studies have suggested that GCs inhibit the migration and invasion of GBM cells through the induction of MAPK phosphatase 1 (MKP-1). Macrophage migration inhibitory factor (MIF), an endogenous GC antagonist is up-regulated in GBMs. Recently, MIF has been involved in tumor growth and migration/invasion and specific MIF inhibitors have been developed on their capacity to block its enzymatic tautomerase activity site. In this study, we characterized several glioma cell lines for their MIF production. U373 MG cells were selected for their very low endogenous levels of MIF. We showed that dexamethasone inhibits the migration and invasion of U373 MG cells, through a glucocorticoid receptor (GR)- dependent inhibition of the ERK1/2 MAPK pathway. Oppositely, we found that exogenous MIF increases U373 MG migration and invasion through the stimulation of the ERK1/2 MAP kinase pathway and that this activation is CD74 independent. Finally, we used the Hs 683 glioma cells that are resistant to GCs and produce high levels of endogenous MIF, and showed that the specific MIF inhibitor ISO-1 could restore dexamethasone sensitivity in these cells. Collectively, our results indicate an intricate pathway between MIF expression and GC resistance. They suggest that MIF inhibitors could increase the response of GBMs to corticotherapy.

Sensitization of endothelial cells to TNFα-induced death

RESUME L'angiogénèse tumorale est un processus essentiel au développement des tumeurs. Les intégrines, molécules d'adhésions transmembranaires, sont d'importants effecteurs de l'angiogenèse. En permettant l'adhésion à la matrice extra-cellulaire, les intégrines transmettant des signaux de survie, de migration, et de prolifération. Le facteur de nécrose tumorale α (TNFα) est utilisé pour le traitement régional de cancers chez l'homme. II agit en détruisant sélectivement les vaisseaux angiogéniques. Cependant, son administration systémique chez l'homme est limitée par les réactions de vaso-dilatation sévères qu'il provoque. Le but de mon travail fut de rechercher des conditions permettant la sensibilisation des cellules endothéliales au TNFα et qui pourraient être applicables en clinique, ceci afin d'accroître l'efficacité de cette molécule. Nous avons testé la possibilité d'interférer avec les signaux de survie provenant des intégrines. Pour cela, des cellules endothéliales furent cultivées dans des conditions d'adhésion ou en suspension, ou alors exposées dans des conditions d'adhésion au zoledronate (biphosphonate contenant du nitrogène). Dans ces conditions, les effets du TNFα sur les cellules endothéliales furent étudiés, en particulier l'induction de la mort cellulaire. Dans ce travail, nous montrons que le zoledronate sensibilise les cellules endothéliales à la nécrose induite par TNFα. Cet effet s'accompagne de l'inhibition de la phosphorylation de FAK, PKB, et JNK, ainsi que de l'inhibition de la prénylation des protéines. En revanche, l'activation de NF-kB et p38 n'est pas perturbée. La restoration de la prénylation des protéines empêche la mort des HUVEC traitées par zoledronate et TNFα, et rétablit la phosphorylation de FAK, PKB, et JNK. Des essais d'angiogénèse in vivo montrent que le zoledronate inhibe l'angiogénèse induite par FGF-2. Le zoledronate encapsulé dans des liposomes permet de ralentir la croissance tumorale et synergise avec le TNFα en l'inhibant. L'inihibtion de la prénylation des protéines est un des mécanismes de sensibilisation du zoledronate au TNFα. In vivo, la synergie de leur association sur la croissance tumorale est efficace. Ces résultats encouragent la poursuite de l'étude des effets de ces deux drogues sur la croissance tumorale. SUMMARY The formation of tumor-associated vessels is essential for tumor progression. Cell adhesion molecules of the integrin family are important mediators of angiogenesis, by providing adhesive signals necessary for endothelial cell migration, proliferation and survival. Anti-angiogenic therapies are currently considered as highly promising in the treatment of human cancer. Tumor Necrosis Factor α (TNFα) is used for the regional treatment of human cancer, whose mechanisms of action involved selective disruption of angiogenic tumor vessels. Systemic administration of TNFα in humans, however, induces a severe inflammatory condition that prevents its use far the treatments of tumors localized outside of limbs. The aim of my work was to find strategies to sensitize angiogenic endothelial cells to TNFα-induced death, which could be potentially translated into clinical setting to improve the therapeutic efficacy of TNFα. We specifically tested the hypothesis whether interference with integrin-mediated adhesion and signaling may sensitize endothelial cells to TNFα-induced death. To test this hypothesis we cultured endothelial cells (EC) under conditions of cell-matrix or cell-cell adhesion or exposed matrix-adherent EC to the nitrogen-containing bisphosphonate zoledronate, and characterized the effect on TNFα-mediated signaling events and cell death. We show that zoledronate sensitizes HUVEC to TNFα-induced necrosis-like programmed cell death. This effect was associated with suppression of sustained phosphorylation of PKB and JNK and decreased protein prenylation, whereas TNFα-induced activation of NF-kB and p38 were not inhibited. Restoration of protein prenylation rescued HUVEC from zoledronate and TNFα-induced death, and restored FAK, PKB and JNK phosphorylation. By using in vivo angiogenesis assay we showed that zoledronate suppressed FGF-2-induced angiogenesis. Liposome-encapulated zoledronate partially inhibited tumor growth and synergized with TNFα to fully suppress tumor growth. Taken together, this work has identified protein prenylation as a mechanisms by which zoledronate sensitizes endothelial cells to TNFα-induced death in vitro and provides initial evidence that zoledronate synergizes with TNFα in vivo resulting in improved anti-tumor activity. These results warrant further study of the anti-tumor effects of zoledronate and TNFα and should be further studies in view of their clinical relevance.

The role of migration and domestic transmission in the spread of HIV-1 non-B subtypes in Switzerland.

BACKGROUND: By analyzing human immunodeficiency virus type 1 (HIV-1) pol sequences from the Swiss HIV Cohort Study (SHCS), we explored whether the prevalence of non-B subtypes reflects domestic transmission or migration patterns. METHODS: Swiss non-B sequences and sequences collected abroad were pooled to construct maximum likelihood trees, which were analyzed for Swiss-specific subepidemics, (subtrees including ≥80% Swiss sequences, bootstrap >70%; macroscale analysis) or evidence for domestic transmission (sequence pairs with genetic distance <1.5%, bootstrap ≥98%; microscale analysis). RESULTS: Of 8287 SHCS participants, 1732 (21%) were infected with non-B subtypes, of which A (n = 328), C (n = 272), CRF01_AE (n = 258), and CRF02_AG (n = 285) were studied further. The macroscale analysis revealed that 21% (A), 16% (C), 24% (CRF01_AE), and 28% (CRF02_AG) belonged to Swiss-specific subepidemics. The microscale analysis identified 26 possible transmission pairs: 3 (12%) including only homosexual Swiss men of white ethnicity; 3 (12%) including homosexual white men from Switzerland and partners from foreign countries; and 10 (38%) involving heterosexual white Swiss men and females of different nationality and predominantly nonwhite ethnicity. CONCLUSIONS: Of all non-B infections diagnosed in Switzerland, <25% could be prevented by domestic interventions. Awareness should be raised among immigrants and Swiss individuals with partners from high prevalence countries to contain the spread of non-B subtypes.

Macrophage migration inhibitory factor is involved in a positive feedback loop increasing aromatase expression in endometriosis.

Immune-endocrine interplay may play a major role in the pathogenesis of endometriosis. In the present study, we have investigated the interaction between macrophage migration inhibitory factor (MIF), a major pro-inflammatory and growth-promoting factor markedly expressed in active endometriotic lesions, and estradiol (E(2)) in ectopic endometrial cells. Our data showed a significant increase of MIF protein secretion and mRNA expression in endometriotic cells in response to E(2). MIF production was blocked by Fulvestrant, an estrogen receptor (ER) antagonist, and induced by ERα and ERβ selective agonists propyl-pyrazole-triol (PPT) and diarylpropionrile (DPN), respectively, thus demonstrating a specific receptor-mediated effect. Cell transfection with MIF promoter construct showed that E(2) significantly stimulates MIF promoter activity. Interestingly, our data further revealed that MIF reciprocally stimulates aromatase protein and mRNA expression via a posttranscriptional mRNA stabilization mechanism, that E(2) itself can upregulate aromatase expression, and that inhibition of endogenous MIF, using MIF specific siRNA, significantly inhibits E(2)-induced aromatase. Thus, the present study revealed the existence of a local positive feedback loop by which estrogen acts directly on ectopic endometrial cells to upregulate the expression of MIF, which, in turn, displays the capability of inducing the expression of aromatase, the key and rate-limiting enzyme for estrogen synthesis. Such interplay may have a considerable impact on the development of endometriosis.

Targeting the PI3K p110alpha isoform inhibits medulloblastoma proliferation, chemoresistance, and migration.

PURPOSE: The phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in human cancer and plays a crucial role in medulloblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K/Akt signaling as a novel antiproliferative approach in medulloblastoma. EXPERIMENTAL DESIGN: The expression pattern and functions of class I(A) PI3K isoforms were investigated in medulloblastoma tumour samples and cell lines. Effects on cell survival and downstream signaling were analyzed following down-regulation of p110alpha, p110beta, or p110delta by means of RNA interference or inhibition with isoform-specific PI3K inhibitors. RESULTS: Overexpression of the catalytic p110alpha isoform was detected in a panel of primary medulloblastoma samples and cell lines compared with normal brain tissue. Down-regulation of p110alpha expression by RNA interference impaired the growth of medulloblastoma cells, induced apoptosis, and led to decreased migratory capacity of the cells. This effect was selective, because RNA interference targeting of p110beta or p110delta did not result in a comparable impairment of DAOY cell survival. Isoform-specific p110alpha inhibitors also impaired medulloblastoma cell proliferation and sensitized the cells to chemotherapy. Medulloblastoma cells treated with p110alpha inhibitors further displayed reduced activation of Akt and the ribosomal protein S6 kinase in response to stimulation with hepatocyte growth factor and insulin-like growth factor-I. CONCLUSIONS: Together, our data reveal a novel function of p110alpha in medulloblastoma growth and survival.

Thérapie cellulaire régénérative en cardiologie: le futur au présent [Cell-based regenerative therapy in cardiology: the future at present].

Cell-based regenerative therapy treatment of cardiovascular diseases considered as irreversible, as acute myocardial infarction, chronic ischemic heart failure, non-ischemic dilated cardiomyopathy and refractory angina pectoris. Large randomized clinical trials with hard clinical endpoints are still necessary before considering cell-based regenerative therapy as a valuable alternative therapeutic option in cardiology.

Construction and electrophoretic migration of single-stranded DNA knots and catenanes.

In recent years there has been growing interest in the question of how the particular topology of polymeric chains affects their overall dimensions and physical behavior. The majority of relevant studies are based on numerical simulation methods or analytical treatment; however, both these approaches depend on various assumptions and simplifications. Experimental verification is clearly needed but was hampered by practical difficulties in obtaining preparative amounts of knotted or catenated polymers with predefined topology and precisely set chain length. We introduce here an efficient method of production of various single-stranded DNA knots and catenanes that have the same global chain length. We also characterize electrophoretic migration of the produced single-stranded DNA knots and catenanes with increasing complexity.

NSAIDs inhibit alpha V beta 3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis.

Cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism, is overexpressed in many cancers. Inhibition of COX-2 by nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of cancer development in humans and suppresses tumor growth in animal models. The anti-cancer effect of NSAIDs seems to involve suppression of tumor angiogenesis, but the underlying mechanism is not completely understood. Integrin alpha V beta 3 is an adhesion receptor critically involved in mediating tumor angiogenesis. Here we show that inhibition of endothelial-cell COX-2 by NSAIDs suppresses alpha V beta 3-dependent activation of the small GTPases Cdc42 and Rac, resulting in inhibition of endothelial-cell spreading and migration in vitro and suppression of fibroblast growth factor-2-induced angiogenesis in vivo. These results establish a novel functional link between COX-2, integrin alpha V beta 3 and Cdc42-/Rac-dependent endothelial-cell migration. Moreover, they provide a rationale to the understanding of the anti-angiogenic activity of NSAIDs.

Reelin controls progenitor cell migration in the healty and pathological adult brain

Understanding the signals that control migration of neural progenitor cells in the adult brain may provide new therapeutic opportunities. Reelin is best known for its role in regulating cell migration during brain development, but we now demonstrate a novel function for reelin in the injured adult brain. First, we show that Reelin is upregulated around lesions. Second, experimentally increasing Reelin expression levels in healthy mouse brain leads to a change in the migratory behavior of subventricular zone-derived progenitors, triggering them to leave the rostral migratory stream (RMS) to which they are normally restricted during their migration to the olfactory bulb. Third, we reveal that Reelin increases endogenous progenitor cell dispersal in periventricular structures independently of any chemoattraction but via cell detachment and chemokinetic action, and thereby potentiates spontaneous cell recruitment to demyelination lesions in the corpus callosum. Conversely, animals lacking Reelin signaling exhibit reduced endogenous progenitor recruitment at the lesion site. Altogether, these results demonstrate that beyond its known role during brain development, Reelin is a key player in post-lesional cell migration in the adult brain. Finally our findings provide proof of concept that allowing progenitors to escape from the RMS is a potential therapeutic approach to promote myelin repair.

Macrophage migration inhibitory factor deficiency leads to age-dependent impairment of glucose homeostasis in mice.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine produced by many cells and tissues including pancreatic beta-cells, liver, skeletal muscle, and adipocytes. This study investigates the potential role of MIF in carbohydrate homeostasis in a physiological setting outside of severe inflammation, utilizing Mif knockout (MIF-/-) mice. Compared with wild-type (WT) mice, MIF-/- mice had a lower body weight, from birth until 4 months of age, but subsequently gained weight faster, resulting in a higher body weight at 12 months of age. The lower weight in young mice was related to a higher energy expenditure, and the higher weight in older mice was related to an increased food intake and a higher fat mass. Fasting blood insulin level was higher in MIF-/- mice compared with WT mice at any age. After i.p. glucose injection, the elevation of blood insulin level was higher in MIF-/- mice compared with WT mice, at 2 months of age, but was lower in 12-month-old MIF-/- mice. As a result, the glucose clearance during intraperitoneal glucose tolerance tests was higher in MIF-/- mice compared with WT mice until 4 months of age, and was lower in 12-month-old MIF-/- mice. Insulin resistance was estimated (euglycemic-hyperinsulinemic clamp tests), and the phosphorylation activity of AKT was similar in MIF-/- mice and WT mice. In conclusion, this mouse model provides evidence for the role of MIF in the control of glucose homeostasis.

MYADM regulates Rac1 targeting to ordered membranes required for cell spreading and migration

Membrane organization into condensed domains or rafts provides molecular platforms for selective recruitment of proteins. Cell migration is a general process that requires spatiotemporal targeting of Rac1 to membrane rafts. The protein machinery responsible for making rafts competent to recruit Rac1 remains elusive. Some members of the MAL family of proteins are involved in specialized processes dependent on this type of membrane. Because condensed membrane domains are a general feature of the plasma membrane of all mammalian cells, we hypothesized that MAL family members with ubiquitous expression and plasma membrane distribution could be involved in the organization of membranes for cell migration. We show that myeloid-associated differentiation marker (MYADM), a protein with unique features within the MAL family, colocalizes with Rac1 in membrane protrusions at the cell surface and distributes in condensed membranes. MYADM knockdown (KD) cells had altered membrane condensation and showed deficient incorporation of Rac1 to membrane raft fractions and, similar to Rac1 KD cells, exhibited reduced cell spreading and migration. Results of rescue-of-function experiments by expression of MYADM or active Rac1L61 in cells knocked down for Rac1 or MYADM, respectively, are consistent with the idea that MYADM and Rac1 act on parallel pathways that lead to similar functional outcomes.

Role of hepatocyte wounding on " Plasmodium " liver-stage development and survival

RESUME La première étape primordiale au cycle de vie du Plasmodium dans un hôte mammifère est l'invasion des hepatocytes par des sporozoites. L'infection finale des hepatocytes est précédée de la traversée de plusieurs cellules hôtes, rompant les membranes plasmiques et ayant comme résultat la sécrétion des facteurs cytotoliques dans le micro-environnement. Ce matériel endogène libéré est fortement stimulant/immunogène et peut servir de signal de danger initiant des réponses distinctes dans diverses cellules. De nos jours, le caractère essentiel et salutaire de la migration des sporozoites comme étape d'infection du Plasmodium est vivement controversée. Ainsi, notre étude a visé à caractériser l'effet de l'interaction du parasite avec ses cellules hôtes d'un point de vue immunologique. En particulier, nous avons voulu évaluer l'effet de la perte de matériel cellulaire pendant l'infection de Plasmodium sur les hepatocytes primaires de souris et sur des cultures cellulaires HepG2. Nous avons observé que les facteurs cytotoxiques dérivés des cellules endommagés activent NF-κB - un important régulateur de réponse inflammatoires -dans des cellules voisines des cellules endommagés, qui sont des cellules hôtes potentielles pour l'infection finale du parasite. Cette activation de NF-κB s'est produite peu de temps après l'infection et a mené in vitro et in vivo à une réduction d'infection de façon dépendante du temps, un effet qui a pu être compensé par l'addition de BAY11-7082, un inhibiteur spécifique de NF-κB. De plus, aucune activation de NF-κB avec des parasites SPECT-/-, incapables de traverser les hepatocytes, n'a été observée. Nous avons montré parla suite que l'activation de NF-κB induit l'expression de l'enzyme iNOS dans les hepatocytes, qui est responsable d'une diminution des hepatocytes infectés. En outre, les hepatocytes primaires des souris MyD88-/- n'ont montré ni activation de NF-κB, ni expression d'iNOS lors de l'infection, ce qui suggère la participation des membres de famille du Toll/IL-1 récepteur dans la reconnaissance des facteurs cytosoxiques. En effet, le manque de MyD88 a augmenté significativement l'infection in vitro et in vivo. D'autre part, un rôle bénéfique pour l'activation de NF-κB a été évalué. Les cellules infectées étaient plus résistantes contre l'apoptose induite par Fas (CD95/Apo-1) que les cellules non infectées ou les cellules infectées dans lesquelles NF-κB a été bloqué par BAY11-7082 in vitro. Paradoxalement, l'expression d'iNOS contribue à la protection des cellules infectées contre l'apoptose pax Fas, puisque le traitement avec l'inhibiteur spécifique SMT (S-methylisothiourea) a rendu les cellules infectées plus susceptibles à l'apoptose. Un effet bénéfique additionnel pour le parasite est que la plupart des cellules hôtes traversées présentent des peptides du parasite aux cellules T cytotoxiques spécifiques et peuvent donc réorienter la réaction immune spécifique sur les cellules non infectées. Nous montrons que les cellules hôtes endommagés par la migration du parasite induit l'inflammation, qui limite l'ampleur de l'infection. D'autre part, nos données soutiennent que la survie du parasite Plasmodium dans le foie est assurée par une augmentation de la résistance des hepatocytes contre l'apoptose. SUMMARY The first obligatory step of the Plasmodium life cycle in the mammalian host is the invasion of hepatocytes by sporozoites. Final hepatocyte infection involves the penetration of several host cells, whose plasma membranes are ruptured in the process, resulting in the release of cytosolic factors into the microenvironment. This released endogenous material is highly stimulatory / immunogenic and can serve as a danger signal initiating distinct responses in various cells. To date, it is highly controversial whether sporozoite migration through hepatocytes is an essential and beneficial step for Plasmodium infection. Thus, our study aimed at characterizing the effect of the interaction of the parasite with its host cells from an immunological point of view In particular, we wanted to evaluate the effect of cell material leakage during Plasmodium infection on cultured mouse primary hepatocytes and HepG2 cells. We observed that wounded cell-derived cytosolic factors activate NF-κB - a main regulator of host inflammatory responses - in cells bordering wounded cells, which are potential host cells for final parasite infection. This activation of NF-κB occurred shortly after infection and led to a reduction of infection load in a time dependent manner in vitro and in viva, an effect that could be reverted by addition of the specific NF-κB inhibitor BAY11-7082. In addition, no NF-κB activation was observed when SPECT-/- parasites, which are devoid of hepatocyte traversing properties, were used. We provide further evidence that NF-κB activation causes the induction of inducible nitric oxide synthase (iNOS) expression in hepatocytes, and this is, in turn, responsible for a decrease in Plasmodium-infected hepatocytes. Furthermore, primary hepatocytes from MyD88-/- mice showed no NF-κB activation and iNOS expression upon infection, suggesting a role of the Toll/IL-1 receptor family members in sensing cytosolic factors. Indeed, lack of MyD88 significantly increased infection in vitro and in vivo. In a further complementary series of experiments, we assessed a possible beneficial role for the activation of NF-κB. Infected cells were more resistant to Fas (CD95/Apo-1)-mediated apoptosis than uninfected cells or infected cells in which NF-κB was blocked by BAYl1-7082 in vitro. Paradoxically, iNOS expression contributes to the protection of infected cells from Fas-induced apoptosis, since treatment with the specific iNOS inhibitor SMT (S-Methylisothiourea Sulfate) rendered the infected cells more susceptible to apoptosis. An additional beneficial effect of host cell traversal for the parasite is the fact that mainly traversed cells present parasite-derived peptides to specific cytotoxic T cells and therefore may redirect the specific immune response to uninfected cells. In summary, we have shown that host cells wounded by parasite migration induce inflammation, which limits the extent of parasite infection. In addition, our data support the notion that survival of Plasmodium parasites in the liver is mediated by increasing the resistance of hepatocytes to Fas-induced apoptosis.