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Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. While T cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T cell-inflamed tumor microenvironment are not fully understood. We used an unbiased approach to identify tumor-intrinsic mechanisms shaping the immune tumor microenvironment (TME), focusing on pancreatic adenocarcinoma because it is refractory to immunotherapy and excludes T cells from the TME. From human tumors, we identified ephrin-A receptor 2 (EPHA2) as a candidate tumor-intrinsic driver of immunosuppression. Epha2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy. We found that prostaglandin endoperoxide synthase 2 (PTGS2), the gene encoding cyclooxygenase- 2, lies downstream of EPHA2 signaling through TGF-[beta] and is associated with poor patient survival. Ptgs2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy; pharmacological inhibition of PTGS2 was similarly effective. Thus, EPHA2/PTGS2 signaling in tumor cells regulates tumor immune phenotypes; blockade may represent a therapeutic avenue for immunotherapy-refractory cancers. Our findings warrant clinical trials testing the effectiveness of therapies combining EPHA2/TGF-[beta]/PTGS2 pathway inhibitors with antitumor immunotherapy and may change the treatment of notoriously therapy-resistant pancreatic adenocarcinoma., Introduction Immunotherapies, including immune checkpoint blockade (ICB), have led to significant improvement of clinical care for cancer patients (1-4). Patients with melanoma, lung adenocarcinoma, or kidney cancer have a 20%-40% [...]

Although modifications of gut microbiota with antibiotics (Abx) influence mouse skin and cardiac allografts, its role in orthotopic liver transplantation (OLT) remains unknown. We aimed to determine whether and how recipient Abx pretreatment may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. Mice (C57BL/6) with or without Abx treatment (10 days) were transplanted with allogeneic (BALB/c) cold-stored (18 hours) livers, followed by liver and blood sampling (6 hours). We divided 264 human OLT recipients on the basis of duration of pre-OLT Abx treatment into control (Abx-free/Abx, Introduction Orthotopic liver transplantation (OLT) has become the standard of care for patients with end-stage liver disease or hepatic malignancies (1). Ischemia-reperfusion injury (IRI), a leading cause of early allograft [...]

We previously reported that sevoflurane-induced pica, kaolin ingestion behavior, in rats has the potential to reflect postoperative nausea and vomiting (PONV) in humans. It is well-known that corticosteroids, which inhibit both prostaglandin and leukotriene syntheses due to phospholipase [A.sub.2] inhibition, are effective for reducing PONV; however, the precise mechanisms remain unclear. We investigated the involvement of the prostaglandin or leukotriene pathway in the development of sevoflurane-induced pica. We found that sevoflurane-induced pica was effectively inhibited by pretreatment with a leukotriene receptor antagonist (montelukast) or an inhibitor of 5-lipoxygenase (zileuton), rather than an inhibitor of cyclooxygenase (flurbiprofen). Furthermore, we observed that sevoflurane significantly increased urinary leukotriene excretion and 5-lipoxygenase mRNA expression in the spleen, but not hypothalamus. These results suggest that the production of leukotriene may lead to the development of sevoflurane-induced pica in rats, and that inhibition of the leukotriene pathway could be potentially useful for the treatment of PONV. Key words: leukotriene, 5-lipoxygenase, pica, postoperative nausea and vomiting. Nous avons rapporte precedemment que le comportement d'ingestion de kaolin (pica provoque par le sevoflurane) chez le rat a le potentiel de refleter des nausees et des vomissements pendant la periode postoperatoire (NVPO) chez l'humain. Il est bien connu que les corticosteroides, qui entrainent une inhibition de la synthese des prostaglandines comme des leucotrienes par l'intermediaire de l'inhibition de la phospholipase [A.sub.2], sont efficaces pour attenuer les NVPO; le mode d'action precis demeure cependant a clarifier. Nous avons etudie la contribution des voies de signalisation des prostaglandines ou des leucotrienes dans l'apparition du pica provoque par le sevoflurane. Nous avons observe que contrairement aux effets d'un inhibiteur de la cyclooxygenase (le flurbiprofene), le pica provoque par le sevoflurane etait inhibe efficacement avec l'administration prealable d'un antagoniste des recepteurs des leucotrienes (le montelukast) ou d'un inhibiteur de la 5-lipoxygenase (le zileuton). En outre, nous avons observe que le sevoflurane entrainait une augmentation importante de l'excretion urinaire des leucotrienes, ainsi que de l'expression en ARNm de la 5-lipoxygenase dans la rate, mais pas dans l'hypothalamus. Ces resultats laissent entendre que la production de leucotrienes pourrait mener a l'apparition de pica provoque par le sevoflurane, et que l'inhibition de la voie de signalisation des leucotrienes pourrait eventuellement etre utile dans le traitement des NVPO. [Traduit par la Redaction] Mots-cles: leucotrienes, 5-lipoxygenase, pica, nausees et vomissements postoperatoires., Introduction Postoperative nausea and vomiting (PONV) occur in 30% of surgical patients under general anesthesia (Gan 2006). Serotonin 5-H[T.sub.3], neurokinin N[K.sub.1] receptor antagonists, and corticosteroids are used to reduce the [...]

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that are crucial for the regulation of immune responses in cancer. These cells contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite recent advances in the understanding of PMN-MDSC biology, the mechanisms responsible for the pathological activation of neutrophils are not well defined, and this limits the selective targeting of these cells. Here we report that mouse and human PMN-MDSCs exclusively upregulate fatty acid transport protein 2 (FATP2). Overexpression of FATP2 in PMN-MDSCs was controlled by granulocyte-macrophage colony-stimulating factor, through the activation of the STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSCs. The main mechanism of FATP2-mediated suppressive activity involved the uptake of arachidonic acid and the synthesis of prostaglandin E.sub.2. The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSCs and substantially delayed tumour progression. In combination with checkpoint inhibitors, FATP2 inhibition blocked tumour progression in mice. Thus, FATP2 mediates the acquisition of immunosuppressive activity by PMN-MDSCs and represents a target to inhibit the functions of PMN-MDSCs selectively and to improve the efficiency of cancer therapy. The lipid transporter FATP2 reprograms neutrophils to polymorphonuclear myeloid-derived suppressor cells by mediating the uptake of arachidonic acid and promoting the synthesis of prostaglandin E.sub.2., Author(s): Filippo Veglia [sup.1] , Vladimir A. Tyurin [sup.2] , Maria Blasi [sup.3] , Alessandra De Leo [sup.4] , Andrew V. Kossenkov [sup.1] , Laxminarasimha Donthireddy [sup.1] , Tsun Ki [...]

During the pathogenetic process of varied kidney diseases, renal tubules are the major sites in response to detrimental insults, including pro-inflammatory stimuli. MicroRNA-204-5p (miR-204-5p) can be detected in the renal tubular epithelial cells in the normal kidney; its expression, however, is downregulated in the kidney with pathological changes. This study aimed to investigate the role of miR-204-5p in interleukin 6 (IL6) mediated inflammatory response and chemokine production in HK-2 renal tubular cells. In HK-2 cells, the expression of miR-204-5p was downregulated in response to exogenous pro-inflammatory stimulus, tumor necrosis factor [alpha] (TNF[alpha]), or IL1[beta], while that of IL6 receptor [alpha] (IL6R) was upregulated. Dual-luciferase results confirmed that miRNA-204-5p directly targeted IL6R. In addition to suppressing IL6R expression, miRNA-204-5p agomir also inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in HK-2 cells exposed to exogenous IL6. Further, miRNA-204-5p suppressed the overproduction of pro-inflammatory mediators (cyclooxygenase 2 and prostaglandin [E.sub.2]) and chemokines (C-C motif chemokine ligand 2 and C-X-C motif chemokine ligand 8). The anti-inflammatory effects of miRNA-204-5p were attenuated when IL6R was reexpressed in HK-2 cells. Collectively, our study reveals that miR-204-5p inhibits the inflammation and chemokine generation in renal tubular epithelial cells by modulating the IL6/IL6R axis. Key words: microRNA-204-5p, IL6R, renal tubular epithelial cells, inflammation, chemokine generation. Durant le processus pathogenique qui mene au developpement de diverses maladies renales, les tubules sont les principaux sites endommages par differentes agressions, y compris par les stimulus pro-inflammatoires. Le microARN-204-5p (miR-204-5p) peut etre detecte dans les cellules epitheliales tubulaires renales du rein normal, mais son expression est toutefois regulee a la baisse dans le rein pathologique. Cette etude visait a examiner le role du miR-204-5p sur la reponse inflammatoire mediee par l'interleukine-6 (IL6) et la production de chimiokines chez les cellules tubulaires renales HK-2. L'expression du miR-204-5p etait regulee a la baisse dans ces cellules en reponse a un stimulus pro-inflammatoire exogene, soit le facteur de necrose tumorale [alpha] (TNF[alpha]) ou l'IL1[beta], alors que le recepteur de l'IL6 [alpha] (IL6R) etait regule a la hausse. Les resultats d'un dosage double de la luciferase confirmaient que le miR-204-5p ciblait directement l'IL6R. En plus de supprimer l'expression de l'IL6R, un miR-204-5p synthetique (agomir) inhibait aussi la phosphorylation de STAT3 chez les cellules HK-2 exposees a l'IL6 exogene. En outre, le miR-204-5p supprimait la surproduction de mediateurs (cyclooxygenase 2 et prostaglandine E2) et de chimiokines (CCL2 et CXCL8) pro-inflammatoires. Les effets anti-inflammatoires du miR-204-5p etaient attenues lorsque l'IL6R etait reexprime dans les cellules HK-2. Dans son ensemble, l'etude des auteurs revele que le miR-204-5p inhibe l'inflammation et la production de chimiokines dans les cellules epitheliales tubulaires renales en modulant l'axe IL6/IL6R. [Traduit par la Redaction] Mots-cles: microARN-204-5p, IL6R, cellules epitheliales tubulaires renales, inflammation, production de chimiokine., Introduction MicroRNAs (miRNAs) are a group of small noncoding RNAs (19-23 nt) that regulate gene expression. As epigenetic regulators, miRNAs participate not only in the development and homeostasis of the [...]

Preterm birth ( Key words: cyclooxygenase, cyclooxygenase inhibitors, preterm, labour, pregnancy, prostaglandins, tocolysis, myometrium, decidua, fetal membranes. La naissance prematuree ( Mots-cles : cyclooxygenase, inhibiteurs de la cyclooxygenase, premature, travail, grossesse, prostaglandines, tocolyse, myometre, deciduale, membranes fretales., Introduction Preterm birth ( Indeed, administration of the nonselective COX inhibitor indomethacin to women in preterm labour led to a dramatic cessation of uterine contractions (Zuckerman et al. 1974; Gyoiy [...]

Inflammation is the body's response to injury and infection, involving a complex biological response of the somatosensory, immune, autonomic, and vascular systems. Inflammatory mediators such as prostaglandin, proinflammatory cytokines, and chemokines induce pain via direct activation of nociceptors, the primary sensory neurons that detect noxious stimuli. Neurogenic inflammation is triggered by nerve activation and results in neuropeptide release and rapid plasma extravasation and edema, contributing to pain conditions such as headache. Neuroinflammation is a localized inflammation in the peripheral nervous system (PNS) and central nervous system (CNS). A characteristic feature of neuroinflammation is the activation of glial cells in dorsal root ganglia, spinal cord, and brain which leads to the production of proinflammatory cytokines and chemokines in the PNS and CNS that drives peripheral sensitization and central sensitization. Here, we discuss the distinct roles of inflammation, neurogenic inflammation, and neuroinflammation in the regulation of different types of pain conditions, with a special focus on neuroinflammation in postoperative pain and opioid-induced hyperalgesia., Author(s): Megumi Matsuda [sup.1] [sup.2] , Yul Huh [sup.1] , Ru-Rong Ji [sup.1] Author Affiliations: (Aff1) 0000000100241216, grid.189509.c, Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, [...]

In this issue of the JCI, Panigrahy et al. demonstrate that preoperative administration of the antiinflammatory drug ketorolac or specialized proresolving mediators (SPM) called resolvins increases disease-free survival rates and prevents metastasis after surgery and chemotherapy in mouse models of cancer. The antitumor response was partially mediated by tumor- specific T cell immunity and immunological memory., When treatment also promotes disease A century after Virchow hypothesized the association between inflammation and cancer, it is becoming evident that inflammatory mediators lead to cancer progression and metastasis (1). [...]

Chronic unresolved inflammation contributes to the development of nonalcoholic steatohepatitis (NASH), a disorder characterized by lipotoxicity, fibrosis, and progressive liver dysfunction. In this issue of the JCI, Han et al. report that maresin 1 (MaR1), a proresolving lipid mediator, mitigates NASH by reprograming macrophages to an antiinflammatory phenotype. Mechanistically, they identified retinoic acid-related orphan receptor [alpha] (ROR[alpha]) as both a target and autocrine regulator of MaR1 production. Because NASH is associated with many widely occurring metabolic diseases, including obesity and type 2 diabetes, identification of this endogenous protective pathway could have broad therapeutic implications., Inflammation and its resolution: role of maresins Acute inflammation is a temporally coordinated host response to invading pathogens and tissue injury. Instructed by endogenous mediators, distinct leukocyte subsets sequentially follow [...]