The receptor NLRP3 is involved in the formation of the NLRP3 inflammasome that activates caspase-1 and mediates the release of interleukin 1β (IL-1β) and IL-18. Whether NLRP3 can shape immunological ...function independently of inflammasomes is unclear. We found that NLRP3 expression in CD4(+) T cells specifically supported a T helper type 2 (TH2) transcriptional program in a cell-intrinsic manner. NLRP3, but not the inflammasome adaptor ASC or caspase-1, positively regulated a TH2 program. In TH2 cells, NLRP3 bound the Il4 promoter and transactivated it in conjunction with the transcription factor IRF4. Nlrp3-deficient TH2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. Our results demonstrate the ability of NLRP3 to act as a key transcription factor in TH2 differentiation.
Myeloid-derived suppressor cells (MDSCs) have been identified in humans and mice as a population of immature myeloid cells with the ability to suppress T cell activation. They accumulate in ...tumor-bearing mice and humans and have been shown to contribute to cancer development. Here, we have isolated tumor-derived exosomes (TDEs) from mouse cell lines and shown that an interaction between TDE-associated Hsp72 and MDSCs determines the suppressive activity of the MDSCs via activation of Stat3. In addition, tumor-derived soluble factors triggered MDSC expansion via activation of Erk. TDE-associated Hsp72 triggered Stat3 activation in MDSCs in a TLR2/MyD88-dependent manner through autocrine production of IL-6. Importantly, decreasing exosome production using dimethyl amiloride enhanced the in vivo antitumor efficacy of the chemotherapeutic drug cyclophosphamide in 3 different mouse tumor models. We also demonstrated that this mechanism is relevant in cancer patients, as TDEs from a human tumor cell line activated human MDSCs and triggered their suppressive function in an Hsp72/TLR2-dependent manner. Further, MDSCs from cancer patients treated with amiloride, a drug used to treat high blood pressure that also inhibits exosome formation, exhibited reduced suppressor functions. Collectively, our findings show in both mice and humans that Hsp72 expressed at the surface of TDEs restrains tumor immune surveillance by promoting MDSC suppressive functions.
The receptor NLRP3 is involved in the formation of the NLRP3 inflammasome that activates caspase-1 and mediates the release of interleukin 1β (IL-1β) and IL-18. Whether NLRP3 can shape immunological ...function independently of inflammasomes is unclear. We found that NLRP3 expression in CD4.sup.+ T cells specifically supported a T helper type 2 (T.sub.H2) transcriptional program in a cell-intrinsic manner. NLRP3, but not the inflammasome adaptor ASC or caspase-1, positively regulated a T.sub.H2 program. In T.sub.H2 cells, NLRP3 bound the I/4 promoter and transactivated it in conjunction with the transcription factor IRF4. W/rp3-deficient T.sub.H2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. Our results demonstrate the ability of NLRP3 to act as a key transcription factor in T.sub.H2 differentiation.
The receptor NLRP3 is involved in the formation of the NLRP3 inflammasome that activates caspase-1 and mediates the release of interleukin 1 beta (IL-1 beta ) and IL-18. Whether NLRP3 can shape ...immunological function independently of inflammasomes is unclear. We found that NLRP3 expression in CD4 super(+) T cells specifically supported a T helper type 2 (T sub(H)2) transcriptional program in a cell-intrinsic manner. NLRP3, but not the inflammasome adaptor ASC or caspase-1, positively regulated a T sub(H)2 program. In T sub(H)2 cells, NLRP3 bound the Il4 promoter and transactivated it in conjunction with the transcription factor IRF4. Nlrp3-deficient T sub(H)2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. Our results demonstrate the ability of NLRP3 to act as a key transcription factor in T sub(H)2 differentiation.
We investigated the role of proteases in the pathway that leads from specific DNA damage induced by etoposide (VP‐16), a topoisomerase II inhibitor, to apoptotic DNA fragmentation in the U937 human ...leukemic cell line. In a reconstituted cell‐free system, Triton‐soluble extracts from VP‐16‐treated cells induced internucleosomal DNA fragmentation in nuclei from untreated cells. This effect was inhibited by the tetrapeptide Ac‐DEVD‐CHO, a competitive inhibitor of the interleukin‐1 beta‐converting enzyme (ICE)‐related protease CPP32, but was not influenced by Ac‐YVAD‐CHO and Ac‐YVAD‐CMK, two specific inhibitors of ICE. The three tetrapeptides inhibited Fas‐mediated apoptotic DNA fragmentation in the cell‐free system. Internucleosomal DNA fragmentation, triggered by either VP‐16 or an anti‐Fas antibody, was associated with proteolytic cleavage of the poly(ADP‐ribose)polymerase (PARP), a decrease in the level of 32 kDa CPP32 proenzyme and the appearance of the CPP32 p17 active subunit. Conversely, the expression of Ich‐1L, another ICE‐like protease, remained stable in apoptotic U937 cells. Several cysteine and serine protease inhibitors prevented apoptotic DNA fragmentation by acting either upstream or downstream of the DEVD‐sensitive protease(s) activation and PARP cleavage. We conclude that a DEVD‐sensitive step, which could involve CPP32, plays a central role in the proteolytic pathway that mediates apoptotic DNA fragmentation in VP‐16‐treated leukemic cells at the crossing with Fas‐mediated pathway.
Myeloid-derived suppressor cells (MDSCs) have been identified in humans and mice as a population of immature myeloid cells with the ability to suppress T cell activation. They accumulate in ...tumor-bearing mice and humans and have been shown to contribute to cancer development. Here, we have isolated tumor-derived exosomes (TDEs) from mouse cell lines and shown that an interaction between TDE-associated Hsp72 and MDSCs determines the suppressive activity of the MDSCs via activation of Stat3. In addition, tumor-derived soluble factors triggered MDSC expansion via activation of Erk. TDE-associated Hsp72 triggered Stat3 activation in MDSCs in a TLR2/MyD88-dependent manner through autocrine production of IL-6. Importantly, decreasing exosome production using dimethyl amiloride enhanced the in vivo antitumor efficacy of the chemotherapeutic drug cyclophosphamide in 3 different mouse tumor models. We also demonstrated that this mechanism is relevant in cancer patients, as TDEs from a human tumor cell line activated human MDSCs and triggered their suppressive function in an Hsp72/TLR2-dependent manner. Further, MDSCs from cancer patients treated with amiloride, a drug used to treat high blood pressure that also inhibits exosome formation, exhibited reduced suppressor functions. Collectively, our findings show in both mice and humans that Hsp72 expressed at the surface of TDEs restrains tumor immune surveillance by promoting MDSC suppressive functions.
Les projets de « ville durable » se sont aujourd'hui multipliés à travers le monde. Comment interpréter cet engouement généralisé ? Est-ce une nouvelle façon de concevoir les relations entre sociétés ...urbaines et environnements naturels ? Dans un contexte d'accélération de l’urbanisation, plutôt que d’acter l’inauguration de nouvelles politiques urbaines, la nécessité d’une analyse des pratiques, représentations et discours de la durabilité urbaine, assortie d’un recul critique s’imposent. C’est l’objectif de cet ouvrage. Il rassemble les travaux actuels de spécialistes en géographie, sociologie et urbanisme, ainsi qu’en architecture, agronomie, lettres, paysagisme, et interroge les dynamiques socio-spatiales de diffusion et de traduction du mot d’ordre désormais mondial de « durabilité urbaine », sur des aires différenciées, en conjuguant les regards « macro » et « micro ». Confrontant de façon originale villes du nord et villes du sud, l’ouvrage donne des clés de compréhension sur la façon dont le projet de « ville durable » a pu devenir le symbole de ce contre quoi il est censé lutter : un « verdissement » inégal de la ville, facteur de ségrégation sociale. Si une ville naturalisée apparaît bien au cœur de la « ville durable », elle procède moins de l’application d’un paradigme idéologique, d’une régulation politique « par le haut » que d’une mosaïque d’initiatives, croisant ambiances, pratiques sociales et récits ordinaires.
Although the function and significance of tumor-infiltrating dendritic cells (TIDC) in the immune response to tumor have never been clearly demonstrated, their location suggests that they play a ...critical role in the presentation of tumor antigen to specific T cells. We studied the morphological and functional characteristics of interstitial dendritic cells (DC) located inside tumors obtained by injection of cancer cells into syngeneic rats. Single and double immunostaining of tumor sections revealed a dense network of cells which expressed class II major histocompatibility complex (MHC II) molecules. Cell morphology and surface markers were characteristic of DC populations in other tissues. These DC were in close contact with tumor cells and increased in number as the tumor grew larger. Unexpectedly, a subpopulation of morphologically characteristic TIDC expressed both CD8 and MHC II molecules. TIDC were purified from tumors by gradient centrifugation and immunobeads and characterized by morphology, ultrastructural study and surface markers studied by flow cytometry. TIDC were negative for the CD5 molecule (a pan T cell marker), and were not labeled with 3.2.3 monoclonal antibody (mAb) (an NK cell marker) or with Ki-M2R mAb (a macrophage marker). A subpopulation of TIDC expressed the CD8 molecule, confirming the in situ results. TIDC expressed high levels of class I and class II MHC molecules and the adhesion molecule ICAM-1. This expression is compatible with effective antigen presenting function. Purified TIDC triggered rapid and high levels of proliferation of tumor-immune T cells in vitro, demonstrating the potential of these cells to constitutively process and present tumor-associated antigens.
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