Literatura académica sobre el tema "Il-33 hiv"

Abstract Development of an effective HIV vaccine is dependent on the quantity and quality of HIV Envelope specific antibody at the mucosal sites. Priming of the oral mucosa is a promising approach to generate mucosal antibody at HIV entry sites. Our recent work in mice has demonstrated the ability of IL-9 and IL-33, known regulators of mucosal immunity, to promote robust development of HIV Env-specific IgG; in addition they increase the breadth, magnitude, and durability of the Env-specific IgG response when combined with the DNA/protein HIV Env immunogen platform VC10014, which elicits Tier 2 neutralizing antibody in rhesus macaques. We hypothesized that conditioning the tonsil microenvironment with IL-9 or IL-33 would enable the rapid induction of durable and effective mucosal humoral immunity by the VC10014 DNA/protein HIV vaccine platform. Rhesus macaques were primed with VC10014 gp160 DNA plasmids in the absence or presence of IL-9 or IL-33 intra-tonsillar (IT), followed by intramuscular (IM) boosting with the DNA/protein HIV vaccine regimen. IT immunization with IL-9 or IL33 induced plasma Env-specific IgG that was present as early as week 6, mucosal Env-specific IgG and heterologous plasma neutralizing antibody. IL-33 treated animals exhibited the greatest number of germinal centers (GCs) and largest GCs following the first IM boost whereas IL-9 treated animals showed the greatest number of GCs following the second IM boost in the draining lymph nodes. The difference in kinetics, with IL-33 promoting an earlier B cell response, and IL-9 promoting greater magnitude later, may suggest that IL-9 and IL-33 promote the development of qualitatively different B cells subsets and may have synergistic potential in HIV vaccine development. Supported by a grant from NIH (R01DE027245).

Introduction: Interleukin-33 (IL-33) is a cell damage-induced alarmin. The plasma concentration of suppression of tumorogenicity (sST2), a surrogate marker of IL-33 production, is a prognostic marker of cardiovascular disease. Observation: Recently, we reported that sST2 plasma levels were elevated in early HIV-1 infection and linked to markers of microbial translocation and of T cell activation. Results: Here we show that it is not the case in patients with suppressed viremia. Thus, IL-33 plays its alarmin role only during the early phase of the infection.

Abstract Despite virologic suppression by HIV antiretroviral therapy, residual inflammation associated with chronic HIV infection increases the risk of developing cardiovascular disease. Monocytes have been shown to be major players in the development of atherosclerosis due to their proinflammatory responses to oxidized Low Density Lipoproteins. Our study sought to assess the functional properties of monocytes from peripheral blood of HIV-infected individuals. The cohort consisted of 33 HIV(+) subjects on HAART and 14 HIV(-) risk- and age- matched subjects. Our flow cytometry-based functional assay measured monocyte production of IL-1β, IL-8 and IL-6 in the absence of stimulation and in response to LPS or oxLDL. Without stimulation, HIV(+) subjects had a greater frequency of cells producing IL-1β and IL-8. In the presence of either oxLDL or LPS, both groups increased the frequency of responding cells compared to no stimulation, but HIV(+) subjects maintained a higher frequency of IL-1β(+) and IL-8(+) cells compared to HIV(-). There was no IL-6 production in either group in the absence of stimulation, but upon stimulation with either oxLDL or LPS, there was a higher frequency of IL-6 producing cells in the HIV(+) group. The higher level of inflammatory cytokine production in HIV(+) adults compared to HIV(-), both at rest and in the presence of stimulation, may in part account for increased risk of cardiovascular disease seen in the HIV(+) population.

Abstract Induction of a sustained and broad antibody (Ab) response is a major goal in developing a protective HIV vaccine. DNA is an attractive priming strategy when combined with protein or viral vector boosting; however, DNA priming alone fails to induce a substantial Ab response, limiting its potential as a stand-alone immunogen. Using the VC10014 DNA/protein vaccine consisting of gp160 plasmids and gp140 proteins derived from an HIV clade B infected subject who developed broadly neutralizing serum Abs, and which has been previously shown to induce Tier 2 heterologous neutralizing Abs in rhesus macaques, we screened a panel of factors in C57BL/6 mice for their ability to enhance the Env-specific Ab response. IL-33, an alarmin, emerged as the lead candidate. The addition of recombinant IL-33 during the gp160 DNA priming phase dramatically changed the kinetics of the Ab response, inducing serum gp120-specific IgG (>1:12,500 titer) after a single DNA immunization, which was not detectable in mice that did not receive IL-33 (p<0.0001). Then following boosting with DNA/protein coimmunization in Alum, gp120-specific IgG levels were extraordinarily durable, remaining stable even at 6 weeks after final immunization compared to mice not receiving IL-33 (p<0.0001), in which they rapidly declined. IL-33 also increased the cross-clade breadth and avidity of the serum gp120-specific IgG response. Analysis of the Env-specific B cell immunoglobulin repertoire and the IL-33 mechanism of action is ongoing. These results demonstrate the profound effect that priming conditions can have on the quality of the Env-specific antibody response.

Histoplasmosis and pneumocystosis co-infections have been reported mainly in immunocompromised humans and in wild animals. The immunological response to each fungal infection has been described primarily using animal models; however, the host response to concomitant infection is unknown. The present work aimed to evaluate the pulmonary immunological response of patients with pneumonia caused either by Histoplasma capsulatum, Pneumocystis jirovecii, or their co-infection. We analyzed the pulmonary collectin and cytokine patterns of 131 bronchoalveolar lavage samples, which included HIV and non-HIV patients infected with H. capsulatum, P. jirovecii, or both fungi, as well as healthy volunteers and HIV patients without the studied fungal infections. Our results showed an increased production of the surfactant protein-A (SP-A) in non-HIV patients with H. capsulatum infection, contrasting with HIV patients (p < 0.05). Significant differences in median values of SP-A, IL-1β, TNF-α, IFN-γ, IL-18, IL-17A, IL-33, IL-13, and CXCL8 were found among all the groups studied, suggesting that these cytokines play a role in the local inflammatory processes of histoplasmosis and pneumocystosis. Interestingly, non-HIV patients with co-infection and pneumocystosis alone showed lower levels of SP-A, IL-1β, TNF-α, IFN-γ, IL-18, IL-17A, and IL-23 than histoplasmosis patients, suggesting an immunomodulatory ability of P. jirovecii over H. capsulatum response.

A global outbreak of predominantly sexually transmitted mpox infections, outside endemic regions, was reported in May 2022. Thereafter, risk groups were vaccinated against smallpox, a structurally related orthopoxvirus. In the current study, we analyzed T cell responses against peptides derived from orthopoxviruses in 33 HIV-positive patients after two vaccinations against smallpox and in 10 patients after mpox infection. We established an ELISpot assay, detecting either the secretion of the pro-inflammatory cytokine interferon (IFN)-γ or interleukin (IL)-2. After vaccination, 21 out of 33 patients (64%) showed specific IFN-γ secretion and 18 (55%) specific IL-2 secretion, defined as >3-fold higher specific value than negative control and at least 4 spots above the negative control. After mpox infection, all patients showed specific IFN-γ secretion and 7 out of 10 (70%) IL-2 secretion. In vaccinated patients, IFN-γ responses were significantly lower than in patients with mpox infection (median response 4.5 vs. 21.0 spots, p < 0.001). The same trend was observed for IL-2 responses. After mpox infection, IL-2 ELISpot results positively correlated with CD8+ T cells (p < 0.05). Thus, T cell responses were detectable in two thirds of HIV-positive patients after vaccination and were even more abundant and vigorous after mpox infection.

Despite long term antiretroviral therapy (ART), insulin resistance (IR) is common among people living with HIV/AIDS (PLWHA) exposing this population to a greater risk of cardiometabolic complications when compared to their uninfected counterparts. We previously identified an expansion in monocyte subpopulations in blood that were linked to the degree of IR in persons with HIV on stable ART. In this study, we directly assessed monocyte inflammatory functional properties from PLWHA on ART (n = 33) and HIV-uninfected controls (n = 14) of similar age, gender, and cardiovascular disease risk and determined the relationship with IR (homeostatic model assessment-insulin resistance (HOMA-IR)), calculated from fasting blood glucose and insulin measurements. Peripheral blood mononuclear cells were stimulated with oxidized low-density lipoproteins (oxLDL) and polyfunctional monocyte cytokine responses (IL-1β, IL-6, IL-8, or TNF-α) were determined by flow cytometry. Higher monocyte IL-1β and IL-8 responses to oxLDL were associated with higher IR in PLWHA but not in the control group. We observed that higher basal monocyte cytokine responses were associated with both duration since HIV diagnosis and ART initiation. In the management of IR in chronic HIV, strategies lowering monocyte IL-1β and IL-8 responses should be considered in addition to ART in order to limit adverse cardio-metabolic outcomes.

Aim: The objective of this study was to investigate the levels of IL-10 in the gingival crevicular fluid in HIV-1 positive patients with chronic periodontitis and to compare with HIV-1 negative patients with chronic periodontitis, also to correlate clinical periodontal parameters, viral load and count of CD4+ and CD8+ lymphocytes (LTCD4+ and LTCD8+). Methods: 33 patients were selected and splitted into two groups: 16 HIV-1 positive patients and 17 HIV-1 negative patients and all with chronic periodontitis. The clinical periodontal parameters recorded were: Probing Depth (PD) and Clinical Attachment Level (CAL); the sistemical parameters LTCD4+, LTCD8+ and viral load were analized by the gingival crevicular fluid collected from all patients. Enzyme-linked immunosorbent assay (ELISA) was used to determine the concentrations of Interleukin (IL)-10. For the statistical analysis the Student t, Mann-Whitney and Spearman tests were performed. IL-10 levels were significantly lower in both patients groups. Results: There was statistical difference betwen groups for probing depth (p=0.015) and clinical attachment level (p=0.011), no significant correlation was found among the analyzed variables. Conclusion: The IL-10 levels in HIV-1 positive patients had no influence in periodontal and medical parameters.

Diabetes mellitus can induce release of free radicals and oxidative stress, which can trigger production of cytokines. Vernonia amygdalina has antidiabetic activity due to its phytochemical constituents. This work was designed to determine possible immunological alterations in the plasma levels of TNF-α and Interleukin-10 (IL-10) in the traditional application of V. amygdalina (Ewuro) leaves in the treatment of diabetes mellitus. The study populations include all 33 diabetes mellitus patients (51-67 years; male, 21; female, 12) who had not commenced any form of medication or treatment and received herbal treatment in 10 herbal homes of Saki West, a local government area in Nigeria. Twenty-seven agematched volunteers who were treated on insulin medication in the hospital almost within the same period were also investigated. Patients who were positive to acid-fast bacilli sputum test, Plasmodium spp., identification, HBsAg, anti-HCV, and HIV-1 p24 assays were not included. Plasma TNF-α, IL-10, HBsAg, anti-HCV, and HIV-1 p24 were determined in the patients by ELISA while identification of acid-fast bacilli and Plasmodium spp. were carried out by Ziehl-Neelsen and Giemsa thick blood-film staining, respectively. There was a significant decrease in the plasma levels of TNF-α, IL-10, and glucose in diabetes mellitus patients after the administration of raw liquid extract of V. amygdalina and insulin compared to their basal samples before the commencement of the treatment (p < 0.05). The work revealed a significant increase in plasma TNF-α, IL-10, and glucose in diabetes patients, which returned to normal plasma values after treatment using raw liquid extract of V. amygdalina leaves and insulin.

Depuis les thérapies antirétrovirales (ART), les principales causes de mortalité et de morbidité sont liées à des pathologies non liées aux SIDA qui sont dûes à un niveau d’inflammation chronique de bas bruit. Cette inflammation est liée entre autre à la persistance de la perte d’homéostasie intestinale qui conduit à des translocations microbiennes dans la circulation systémique. En effet, les sujets traités et infectés par le VIH présentent une déplétion sévère et massive des lymphocytes T CD4+, en particulier dans le tissu lymphoïde associé à l'intestin (GALT) une altération de la barrière épithéliale et une fibrose au niveau des ganglions intestinales.Le récepteur sST2, un récepteur leurre de l'alarmine IL-33, constitue un facteur prédictif important de la mortalité toutes causes confondues, chez les patients séropositifs sous traitement antirétroviral. L'IL-33, précédemment connue comme un moteur des réponses immunitaires Th2, est désormais reconnue comme un adjuvant cytokinique de type "switch-hitting". Libérée par les cellules endommagées, elle favorise l'homéostasie tissulaire; notamment IL-33 permet de restaurer l'intégrité de la muqueuse intestinale après des lésions épithéliales d'origine virale. De plus, IL-33 renforce les réponses immunitaires Th1 pour éliminer les agents pathogènes, elle agit sur les lymphocyes T CD8+ qui expriment ST2. Les Tregs tissulaires induites par l'IL-33 médient la réparation par la libération d'amphiréguline (AREG), un facteur de croissance semblable à l'EGF.Dans cette thèse, nous sommes intéressés à l’axe IL-33/ST2 dans la réparation tissulaire et sur son rôle sur les lymphocytes CD8+ chez des patients traités et infectés par le VIH.Dans une première étude, nous avons analysé si la persistance des lésions intestinales pouvait s'expliquer par la dérégulation de la réparation tissulaire. Dans une deuxième étude, nous avons cherché à caractériser les cellules T CD8 exprimant ST2 et à évaluer le rôle de l'IL-33 sur la réponse T CD8 spécifique du VIH. Les taux plasmatiques de sST2 étaient élevés. Les expressions de l'ARNm et de la protéine IL-33 sont élevées dans la muqueuse intestinale des patients VIH, alors qu'elles étaient indétectables dans leur plasma. L'IL-33 était associée à une augmentation de la fibrose et de l'activation immunitaire tandis que la restauration des T CD4+ a diminué . La caractérisation des Tregs tissulaires a révélé deux populations. Au sein des lymphocytes de la lamina propria (LPL), la fréquence des Tregs ST2+ était augmentés chez les patients HIV traités et cette population de Treg est celle qui produit majoritairement de l’'AREG. Nous avons observé une absence des Tregs qui produisent de l'AREG parmi les LPL des patients HIV traités.Dans une deuxième étude, la caractérisation des cellules T CD8+ exprimant ST2 dans les cellules mononucléées sanguines périphériques chez les patients infectés par le VIH a permis de déterminer que cette population est cytotoxique avec un phénotype effecteur (CD45RA+ CCR7-) et une forte capacité à proliférer après stimulation du TCR. Nous avons montré que ces cellules conservaient une forte expression de ST2 par rapport aux donneurs sains après 5 jours de culture. Ensuite, nous avons observé une augmentation des réponses cytokines et cytotoxiques spécifiques de GAG et de CEF chez les patients VIH traités après culture avec l'IL-33 comme l’attestait l'augmentation de la concentration de l'IFNg, du Granzyme A, du Granzyme B et du sFAS-L dans les surnageants de culture.En résumé, nos résultats mettent en évidence un rôle double de l'IL-33 dans l'infection chronique par le VIH : i) un rôle délétère contribuant à la fibrose dans l'intestin de l'infection et ii) un rôle positif renforçant les réponses spécifiques aux peptides GAG et CEF chez les patients infectés par le VIH sous traitement antirétroviral, indiquant son potentiel en tant qu'immunoadjuvant pour améliorer les réponses vaccinales
HIV has transformed into a chronic disease, since the advent of ART. There is persistence of immune activation and inflammation. It leads to a severe and massive CD4+T cell depletion, particularly in the gut associated lymphoid tissue (GALT). In addition, persistent inflammation exacerbates tissue damage, particularly in the GI tract. Epithelial barrier damage is a prerequisite for leaky gut and microbial translocation, contributing to persistent immune activation in individuals with chronic HIV infection. This is a potential mechanism of impaired CD4 reconstitution by contributing to fibrosis. Moreover, persistent antigen exposure, negative co-stimulation and chronic inflammation despite ART induced viral suppression, leads to CD8 T cell dysfunction.sST2, a decoy receptor of the alarmin, IL-33, is reported to be a significant predictor of all-cause mortality in HIV patients on HAART. IL-33, previously known as a driver of Th2 immune responses, is now recognized as a switch-hitting cytokine adjuvant. Released from damaged cells, it promotes tissue homeostasis and repair. IL-33 functions to restore gut mucosal integrity following viral- or commensals- induced epithelial damage. It enhances Th1 immune responses attempting to eliminate the pathogens, followed by ILCs- and tissue Tregs- induced repair. IL-33 induces protective immunity against viral infections by boosting CD8+ T cell response. IL-33 induced tissue Tregs play a role in tissue repair mediated by the release of Amphiregulin, an EGF-like growth factor.In this thesis, we assessed the involvement of the IL-33/ST2 axis in epithelial tissue repair and its role on CD8+ T cell function. In a first study, we analyzed whether the persistence of gut damage might be explained by the dysregulated tissue repair involving IL-33/ST2 and tissue Treg/Amphiregulin pathways. In a second study, we aimed to characterize CD8 T cells expressing ST2 and to assess the role of IL-33 on HIV specific CD8 T response.Investigations were carried out on mucosal and blood samples from HIV infected patients on c-ART and seronegative healthy controls. Plasma sST2 levels were elevated. IL-33 mRNA and protein expressions revealed elevated expression in the gut mucosa of HIV patients, whereas it was undetectable in the plasma. IL-33 was associated with increased fibrosis and immune activation while decreased CD4 restoration. Phenotypic and functional characterization of tissue Tregs revealed two distinct subsets. ST2+ Tregs were upregulated in the LPL of HIV infected patients and identified as the source of AREG-producing Tregs. However, we observed a functional defect of these cells with a decrease of AREG-producing Tregs in the HIV LPL. Overall, these results suggest that the profound defect of AREG production by Tregs may contribute to the persistence of gut barrier dysfunction despite ART in HIV infected patients.Phenotypic and functional characterization of ST2 expressing CD8 T cells in the PBMCs, deciphered this subset to be a cytotoxic population of effector (RA+ CCR7-) CD8 T cells, with a high capacity to proliferate with TCR stimulation. Their characterization did not differ between HIV infected and healthy controls. CD8 T cells from blood of HIV infected patients on c-ART were shown to maintain a high expression of ST2 compared to healthy donors. These cells were negatively associated with sST2 levels in the plasma. We observed that, after 5 days of culture with IL-33, GAG- and CEF specific CD8 T cells displayed more cytolytic and non-cytolytic responses with an increased concentration of IFNg, Granzyme A, Granzyme B and sFAS-Lin the culture supernatant.To summarize, our results highlight the dual role of IL-33 in chronic HIV infection: i) a deleterious one contributing to fibrosis in the gut of HIV infection and ii) a positive one enhancing GAG- and CEF specific responses in HIV infected patients on c-ART, indicating its potential as an immunoadjuvant for enhancing vaccine responses

Grâce à sa plasticité cellulaire, l'endothélium joue un rôle central dans les processus physiologiques et physiopathologiques. L'équipe s'intéresse au phénotype spécialisé de type HEV qui confère aux cellules endothéliales la capacité unique à recruter un très grand nombre de lymphocytes circulants. Présentes uniquement au niveau des organes lymphoïdes secondaires, les cellules endothéliales de type HEVs sont ainsi garantes de la surveillance immunitaire de l'organisme. Dans certaines conditions inflammatoires ou tumorales, un phénotype de type HEV peut être induit au niveau de tissus non lymphoïdes et pourrait participer au recrutement de cellules immunitaires. De nouvelles thérapeutiques ciblant le contrôle du phénotype HEV pourraient ainsi moduler le recrutement de cellules inflammatoires et améliorer la résolution de ces pathologies. Une partie de mon projet de thèse consiste en l'identification des acteurs cellulaires et moléculaires contrôlant la néogenèse et/ou l'induction phénotypique des HEVs dans un contexte pathologique. J'ai caractérisé un modèle murin d'inflammation cutanée permettant l'induction du phénotype HEV au niveau des vaisseaux du derme enflammé. L'apparition rapide et massive de vaisseaux de type HEV est associée au développement de l'inflammation de type allergique. L'inhibition pharmacologique spécifique des vaisseaux HEVs permet de réduire de manière importante l'infiltrat immunitaire et notamment le nombre d'éosinophiles et de neutrophiles. L'analyse de lignées de souris transgéniques a permis de caractériser un rôle essentiel de la voie de la lymphotoxine et un rôle bi-phasique des lymphocytes dans le contrôle du phénotype vasculaire inflammatoire de type HEV. L'autre partie de mon projet de thèse est fondée sur l'étude d'un facteur de la signature moléculaire des cellules endothéliales HEV : le facteur nucléaire NF-HEV, plus récemment renommée Interleukine 33 (IL-33). Cette cytokine inflammatoire de la famille IL-1, qui chez l'Homme est constitutivement stockée dans le noyau des cellules endothéliales de l'arbre vasculaire sanguin, serait libérée après dommage cellulaire pour orchestrer l'orientation de la réponse immunitaire. Grâce à une lignée reportrice de souris transgéniques développée au laboratoire, nous avons caractérisé le profil d'expression de la protéine chez la souris et notamment l'expression inductible de l'Il-33 murine dans les cellules endothéliales en réponse à certains stimuli inflammatoires. Nous avons par ailleurs démontré, au sein d'un travail collaboratif, que l'Il-33 et son récepteur ST2 régulent l'homéostasie et les mécanismes de réparation de la barrière épithéliale intestinale. L'ensemble de ces travaux souligne ainsi la capacité des cellules endothéliales à s'adapter rapidement aux modifications du microenvironnement. Nous avons notamment caractérisé, en conditions inflammatoires, que la plasticité vasculaire pouvait se traduire par l'adoption d'un phénotype HEV ou par l'induction de l'expression de l'Interleukine-33
Through its cellular plasticity, endothelium plays a crucial role in numerous physiological and pathological processes. The team is interested in the highly specialized HEV phenotype which confers to endothelial cells the unique capacity to recruit high number of circulating lymphocytes. Restricted to secondary lymphoid organs, HEV endothelial cells are major actors for body immune surveillance. In some inflammatory or tumoral conditions, an HEV-like phenotype is induced in non-lymphoid tissues and could mediate immune cell infiltration. Therefore, the control of HEV phenotype could enable the modulation of inflammatory cell recruitment and thus could provide therapeutic benefits in these disorders. A part of my project consists in the identification of the cellular and molecular mechanisms that control HEV neogenesis and/or phenotypic induction in pathological context. I characterized a skin inflammatory mouse model in which HEV phenotype is induced on inflamed dermis blood vessels. This rapid and massive induction of HEV-type vessels is associated to the development of an allergic inflammatory reaction. Pharmacological specific inhibition of HEV vessels allows a drastic reduction of immune infiltrate and notably the number of eosinophils and neutrophils. The study of transgenic mice allows to highlight an essential role of the lymphotoxin pathway and a biphasic role of lymphocytes in the control of HEV-like inflammatory vascular phenotype. The other part of my thesis project is based on the study of a factor of the HEV endothelial cell molecular signature: the nuclear factor NF-HEV, recently renamed Interleukin-33. This IL-1 family inflammatory cytokine, which in Human is constitutively expressed in the nucleus of endothelial cells of the blood vascular tree, would be released after cellular damage to orchestrate orientation of the immune response. Using a transgenic reporter mouse established in our laboratory, we characterized IL-33 expression profile in mice and notably the inducible expression of mouse IL-33 in endothelial cells in response to several inflammatory stimuli. We also have demonstrated, in a collaborative work, that IL-33 and its receptor ST2 regulate intestinal epithelial barrier homeostasis and mucosal healing. Both these results underline the capacity of endothelial cells to adapt rapidly to microenvironment modifications. We especially characterized, in inflammatory conditions, that the vascular plasticity could translate into HEV phenotype adoption or into Interleukine-33 expression

De nombreux travaux mettent en avant que certaines cytokines peuvent être fonctionnelles à la fois dans le milieu extracellulaire et le noyau des cellules. Mon travail de thèse révèle la localisation nucléaire, in vivo, de deux cytokines associées aux cellules endothéliales cuboïdales: la Chimiokine CCL21 et l'Interleukine IL-33. CCL21, exerce ses fonctions chimiotactiques via un récepteur à sept domaines transmembranaires, mais peut aussi présenter une localisation nucléaire, in vivo, grâce à son extension C-terminale basique. Un criblage double hybride nous a permis d'identifier la protéine THAP1, essentielle pour la prolifération des cellules endothéliales, comme une cible nucléaire potentielle. L'IL-33, médiateur puissant de l'inflammation via sa liaison au récepteur ST2, est, en parallèle, un facteur nucléaire, associé in vivo a la chromatine condensée et possédant des capacités de répresseur transcriptionnel in vitro. Ses propriétés sont dépendantes d'un domaine de type homéodomaine
In recent years a number of cytokines and other proteins have been found to be dual function proteins that play roles both extracellularly and in the nucleus. My thesis works demonstrated that two novels proteins could exhibit this dual location: CCL21, the high endothelial venule (HEV)-associated chemokine and IL-33, the recently described member of the IL-1 family. CCL21, which exerts all its functions through G-Protein-Coupled Receptor, also exhibits nuclear localization, in vivo, due to its basic C-terminal extension. Furthermore Two-hybrid screening of an HEV cDNA library identified the THAP1 protein, a regulator of endothelial cell proliferation, as a potential nuclear target of CCL21. We also demonstrated that IL-33, an IL-1-like cytokine that signals via ST2 receptor, is an endothelium-derived, heterochromatin-associated nuclear factor with transcriptional repressor potential. All these properties were found to be mediated by an evolutionarily conserved homedomain-like motif