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1.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34548395

RESUMO

Extracellular adenosine triphosphate (ATP) released by mucosal immune cells and by microbiota in the intestinal lumen elicits diverse immune responses that mediate the intestinal homeostasis via P2 purinergic receptors, while overactivation of ATP signaling leads to mucosal immune system disruption, which leads to pathogenesis of intestinal inflammation. In the small intestine, hydrolysis of luminal ATP by ectonucleoside triphosphate diphosphohydrolase (E-NTPD)7 in epithelial cells is essential for control of the number of T helper 17 (Th17) cells. However, the molecular mechanism by which microbiota-derived ATP in the colon is regulated remains poorly understood. Here, we show that E-NTPD8 is highly expressed in large-intestinal epithelial cells and hydrolyzes microbiota-derived luminal ATP. Compared with wild-type mice, Entpd8-/- mice develop more severe dextran sodium sulfate-induced colitis, which can be ameliorated by either the depletion of neutrophils and monocytes by injecting with anti-Gr-1 antibody or the introduction of P2rx4 deficiency into hematopoietic cells. An increased level of luminal ATP in the colon of Entpd8-/- mice promotes glycolysis in neutrophils through P2x4 receptor-dependent Ca2+ influx, which is linked to prolonged survival and elevated reactive oxygen species production in these cells. Thus, E-NTPD8 limits intestinal inflammation by controlling metabolic alteration toward glycolysis via the P2X4 receptor in myeloid cells.


Assuntos
Adenosina Trifosfatases/fisiologia , Trifosfato de Adenosina/metabolismo , Colite/prevenção & controle , Glicólise , Células Mieloides/metabolismo , Receptores Purinérgicos P2X4/metabolismo , Células Th17/imunologia , Animais , Células Cultivadas , Colite/etiologia , Colite/metabolismo , Colite/patologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/imunologia , Células Mieloides/patologia , Receptores Purinérgicos P2X4/genética , Transdução de Sinais
2.
Gan To Kagaku Ryoho ; 50(2): 239-241, 2023 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-36807184

RESUMO

BACKGROUND: Since a randomized phase Ⅲ trial conducted in the UK in 2009 showed the superiority of gemcitabine (GEM)plus cisplatin(CDDP)combination therapy over GEM monotherapy, GEM plus CDDP combination therapy has been first-line chemotherapy for unresectable biliary tract cancer. METHODS: GEM plus CDDP combination therapy was administered to 29 patients with unresectable biliary tract cancer from 2016 to 2021. RESULTS: The mean age was 71.9 years, male/ female 19/10. The target of chemotherapy was below, local progression was 3 cases, first distant metastasis 7 cases, metastatic recurrence 19 cases. The type of cancer was below, intrahepatic bile duct carcinoma was 8 cases, hepatic hilar bile duct carcinoma 6 cases, gallbladder carcinoma 5 cases, cystic duct carcinoma 1 case, distal bile duct carcinoma 6 cases, and papilla Vater's cancer 3 cases. The dosing period was 23.1 weeks(range 2-52 weeks). The relative dose intensities of GEM and CDDP were 73.7% and 75.1%. The adverse events were below, the hematological toxicities of Grade 3 or higher were neutropenia(65.5%), leukopenia(3.4%), and thrombocytopenia(10.3%). Non-hematological toxicities of Grade 2 or higher were fatigue(13.7%)and skin rash(6.9%). There was no interstitial pneumonia. The disease control rate was 66.7 %(complete response, n=0; partial response, n=6; stable disease, n=10; progressive disease, n=8). CONCLUSION: GEM plus CDDP combination therapy was safe to perform and was an effective treatment for unresectable biliary tract cancer.


Assuntos
Anemia , Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Colangiocarcinoma , Neoplasias da Vesícula Biliar , Neoplasias Gastrointestinais , Neutropenia , Trombocitopenia , Humanos , Masculino , Feminino , Idoso , Gencitabina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina , Neoplasias da Vesícula Biliar/tratamento farmacológico , Cisplatino , Neoplasias dos Ductos Biliares/patologia , Resultado do Tratamento , Neutropenia/induzido quimicamente , Trombocitopenia/etiologia , Colangiocarcinoma/tratamento farmacológico , Neoplasias Gastrointestinais/tratamento farmacológico , Anemia/etiologia , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias do Sistema Biliar/tratamento farmacológico
3.
Proc Natl Acad Sci U S A ; 115(33): 8418-8423, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30061415

RESUMO

The local environment is crucial for shaping the identities of tissue-resident macrophages (Mϕs). When hemorrhage occurs in damaged tissues, hemoglobin induces differentiation of anti-inflammatory Mϕs with reparative function. Mucosal bleeding is one of the pathological features of inflammatory bowel diseases. However, the heme-mediated mechanism modulating activation of intestinal innate immune cells remains poorly understood. Here, we show that heme regulates gut homeostasis through induction of Spi-C in intestinal CX3CR1high Mϕs. Intestinal CX3CR1high Mϕs highly expressed Spi-C in a heme-dependent manner, and myeloid lineage-specific Spic-deficient (Lyz2-cre; Spicflox/flox ) mice showed severe intestinal inflammation with an increased number of Th17 cells during dextran sodium sulfate-induced colitis. Spi-C down-regulated the expression of a subset of Toll-like receptor (TLR)-inducible genes in intestinal CX3CR1high Mϕs to prevent colitis. LPS-induced production of IL-6 and IL-1α, but not IL-10 and TNF-α, by large intestinal Mϕs from Lyz2-cre; Spicflox/flox mice was markedly enhanced. The interaction of Spi-C with IRF5 was linked to disruption of the IRF5-NF-κB p65 complex formation, thereby abrogating recruitment of IRF5 and NF-κB p65 to the Il6 and Il1a promoters. Collectively, these results demonstrate that heme-mediated Spi-C is a key molecule for the noninflammatory signature of intestinal Mϕs by suppressing the induction of a subset of TLR-inducible genes through binding to IRF5.


Assuntos
Colite/tratamento farmacológico , Heme/farmacologia , Intestinos/imunologia , Macrófagos/imunologia , Animais , Receptor 1 de Quimiocina CX3C/fisiologia , Citocinas/biossíntese , Proteínas de Ligação a DNA/fisiologia , Sulfato de Dextrana/toxicidade , Ferro da Dieta/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Receptores Toll-Like/fisiologia , Fator de Transcrição RelA/fisiologia
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