RESUMEN
Tumor-associated macrophages (TAMs) are often associated with chemoresistance and resultant poor clinical outcome in solid tumors. Here, we demonstrated that TAMs-released chemokine-C-C motif chemokine 22 (CCL22) in esophageal squamous cell carcinoma (ESCC) stroma was tightly correlated with the chemoresistance of ESCC patients. TAMs-secreted CCL22 was able to block the growth inhibitory and apoptosis-promoting effects of cisplatin on ESCC cells. Mechanistically, CCL22 stimulated intratumoral diacylglycerol kinase α (DGKα) to produce phosphatidic acid (PA), which suppressed the activity of NADPH oxidase 4 (NOX4) and then blocked the overproduction of intratumoral reactive species oxygen (ROS) induced by cisplatin. CCL22 activated DGKα/nuclear factor-κB (NF-κB) axis to upregulate the level of several members of ATP binding cassette (ABC) transporter superfamily, including ABC sub-family G member 4 (ABCG4), ABC sub-family A member 3 (ABCA3), and ABC sub-family A member 5 (ABCA5), to lower the intratumoral concentration of cisplatin. Consequently, these processes induced the cisplatin resistance in ESCC cells. In xenografted models, targeting DGKα with 5'-cholesterol-conjugated small-interfering (si) RNA enhanced the chemosensitivity of cisplatin in ESCC treatment, especially in the context of TAMs. Our data establish the correlation between the TAMs-induced intratumoral metabolic product/ROS axis and chemotherapy efficacy in ESCC treatment and reveal relevant molecular mechanisms.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Cisplatino/farmacología , Cisplatino/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Diacilglicerol Quinasa/genética , Diacilglicerol Quinasa/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Macrófagos Asociados a Tumores , NADPH Oxidasa 4/genética , Especies Reactivas de Oxígeno , ARN Interferente Pequeño/genética , Proliferación Celular , Quimiocinas/farmacología , Quimiocinas/uso terapéutico , Línea Celular Tumoral , Quimiocina CCL22/farmacología , Quimiocina CCL22/uso terapéuticoRESUMEN
OBJECTIVE: To investigate the effect of baicalin on the growth of extranodal NK/T cell lymphoma (ENKTCL) cells and its related mechanism. METHODS: Normal NK cells and human ENKTCL cells lines SNK-6 and YTS were cultured, then SNK-6 and YTS cells were treated with 5, 10, 20 µmol/L baicalin and set control. Cell proliferation and apoptosis was detected by Edu method and FCM method, respectively, and expressions of BCL-2, Bax, FOXO3 and CCL22 proteins were detected by Western blot. Interference plasmids were designed and synthesized. FOXO3 siRNA interference plasmids and CCL22 pcDNA overexpression plasmids were transfected with PEI transfection reagent. Furthermore, animal models were established for validation. RESULTS: In control group and 5, 10, 20 µmol/L baicalin group, the proliferation rate of SNK-6 cells was (56.17±2.96)%, (51.92±4.63)%, (36.42±1.58)%, and (14.60±2.81)%, respectively, while that of YTS cells was (58.85±2.98)%, (51.38±1.32)%, (34.75±1.09)%, and (15.45±1.10)%, respectively. In control group and 5, 10, 20 µmol/L baicalin group, the apoptosis rate of SNK-6 cells was (5.93±0.74)%, (11.78±0.34)%, (28.46±0.44)%, and (32.40±0.37)%, respectively, while that of YTS cells was (7.93±0.69)%, (16.29±1.35)%, (33.91±1.56)%, and (36.27±1.06)%, respectively. Compared with control group, the expression of BCL-2 protein both in SNK-6 and YTS cells decreased significantly (P<0.001), and the expression of Bax protein increased in SNK-6 cells only when the concentration of baicalin was 20 µmol/L (P<0.001), while that in YTS cells increased in all three concentrations(5, 10, 20 µmol/L) of baicalin (P<0.001). The expression of FOXO3 protein decreased while CCL22 protein increased in ENKTCL cell lines compared with human NK cells (P<0.001), but the expression of FOXO3 protein increased (P<0.01) and CCL22 protein decreased after baicalin treatment (P<0.001). Animal experiments showed that baicalin treatment could inhibit tumor growth. The expression of CCL22 protein in ENKTCL tissue of nude mice treated with baicalin decreased compared with control group (P<0.01), while the FOXO3 protein increased (P<0.05). In addition, FOXO3 silencing resulted in the decrease of FOXO3 protein expression and increase of CCL22 protein expression (P<0.01, P<0.001). CONCLUSION: Baicalin can inhibit proliferation and promote apoptosis of ENKTCL cell lines SNK-6 and YTS, up-regulate the expression of Bax protein, down-regulate the expression of BCL-2 protein, and down-regulate the expression of CCL22 protein mediated by FOXO3. Animal experiment shown that the baicalin can inhibit tumor growth. Baicalin can inhibit the growth and induce apoptosis of ENKTCL cells through FOXO3/CCL22 signaling pathway.
Asunto(s)
Linfoma Extranodal de Células NK-T , Animales , Ratones , Humanos , Linfoma Extranodal de Células NK-T/patología , Proteína Forkhead Box O3/metabolismo , Proteína X Asociada a bcl-2/farmacología , Ratones Desnudos , Transducción de Señal , Apoptosis , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Quimiocina CCL22/farmacologíaRESUMEN
The main pathogenic factor in atopic dermatitis (AD) is Th2 inflammation, and levels of serum CCL17 and CCL22 are related to severity in AD patients. Fulvic acid (FA) is a kind of natural humic acid with anti-inflammatory, antibacterial, and immunomodulatory effects. Our experiments demonstrated the therapeutic effect of FA on AD mice and revealed some potential mechanisms. FA was shown to reduce TARC/CCL17 and MDC/CCL22 expression in HaCaT cells stimulated by TNF-α and IFN-γ. The inhibitors showed that FA inhibits CCL17 and CCL22 production by deactivating the p38 MAPK and JNK pathways. After 2,4-dinitrochlorobenzene (DNCB) induction in mice with atopic dermatitis, FA effectively reduced the symptoms and serum levels of CCL17 and CCL22. In conclusion, topical FA attenuated AD via downregulation of CCL17 and CCL22, via inhibition of P38 MAPK and JNK phosphorylation, and FA is a potential therapeutic agent for AD.
Asunto(s)
Dermatitis Atópica , Animales , Ratones , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/tratamiento farmacológico , Queratinocitos , FN-kappa B/metabolismo , Quimiocina CCL22/metabolismo , Quimiocina CCL22/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Dinitroclorobenceno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Quimiocina CCL17/metabolismo , Quimiocina CCL17/farmacología , Quimiocina CCL17/uso terapéuticoRESUMEN
OBJECTIVE@#To investigate the effect of baicalin on the growth of extranodal NK/T cell lymphoma (ENKTCL) cells and its related mechanism.@*METHODS@#Normal NK cells and human ENKTCL cells lines SNK-6 and YTS were cultured, then SNK-6 and YTS cells were treated with 5, 10, 20 μmol/L baicalin and set control. Cell proliferation and apoptosis was detected by Edu method and FCM method, respectively, and expressions of BCL-2, Bax, FOXO3 and CCL22 proteins were detected by Western blot. Interference plasmids were designed and synthesized. FOXO3 siRNA interference plasmids and CCL22 pcDNA overexpression plasmids were transfected with PEI transfection reagent. Furthermore, animal models were established for validation.@*RESULTS@#In control group and 5, 10, 20 μmol/L baicalin group, the proliferation rate of SNK-6 cells was (56.17±2.96)%, (51.92±4.63)%, (36.42±1.58)%, and (14.60±2.81)%, respectively, while that of YTS cells was (58.85±2.98)%, (51.38±1.32)%, (34.75±1.09)%, and (15.45±1.10)%, respectively. In control group and 5, 10, 20 μmol/L baicalin group, the apoptosis rate of SNK-6 cells was (5.93±0.74)%, (11.78±0.34)%, (28.46±0.44)%, and (32.40±0.37)%, respectively, while that of YTS cells was (7.93±0.69)%, (16.29±1.35)%, (33.91±1.56)%, and (36.27±1.06)%, respectively. Compared with control group, the expression of BCL-2 protein both in SNK-6 and YTS cells decreased significantly (P<0.001), and the expression of Bax protein increased in SNK-6 cells only when the concentration of baicalin was 20 μmol/L (P<0.001), while that in YTS cells increased in all three concentrations(5, 10, 20 μmol/L) of baicalin (P<0.001). The expression of FOXO3 protein decreased while CCL22 protein increased in ENKTCL cell lines compared with human NK cells (P<0.001), but the expression of FOXO3 protein increased (P<0.01) and CCL22 protein decreased after baicalin treatment (P<0.001). Animal experiments showed that baicalin treatment could inhibit tumor growth. The expression of CCL22 protein in ENKTCL tissue of nude mice treated with baicalin decreased compared with control group (P<0.01), while the FOXO3 protein increased (P<0.05). In addition, FOXO3 silencing resulted in the decrease of FOXO3 protein expression and increase of CCL22 protein expression (P<0.01, P<0.001).@*CONCLUSION@#Baicalin can inhibit proliferation and promote apoptosis of ENKTCL cell lines SNK-6 and YTS, up-regulate the expression of Bax protein, down-regulate the expression of BCL-2 protein, and down-regulate the expression of CCL22 protein mediated by FOXO3. Animal experiment shown that the baicalin can inhibit tumor growth. Baicalin can inhibit the growth and induce apoptosis of ENKTCL cells through FOXO3/CCL22 signaling pathway.
Asunto(s)
Animales , Ratones , Humanos , Linfoma Extranodal de Células NK-T/patología , Proteína Forkhead Box O3/metabolismo , Proteína X Asociada a bcl-2/farmacología , Ratones Desnudos , Transducción de Señal , Apoptosis , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Quimiocina CCL22/farmacologíaRESUMEN
Wound healing is a well-coordinated process that involves inflammatory mediators and cellular responses; however, if any disturbances are present during this process, tissue repair is impaired. Chronic wounds are one of the serious long-term complications associated with diabetes mellitus. The chemokine receptor CCR4 and its respective ligands, CCL17 and CCL22, are involved in regulatory T cell recruitment and activation in inflamed skin; however, the role of regulatory T cells in wounds is still not clear. Our aim was to investigate the role of CCR4 and regulatory T cells in cutaneous wound healing in diabetic mice. Alloxan-induced diabetic wild- type mice (diabetic) developed wounds that were difficult to heal, differently from CCR4-/- diabetic mice (CCR4-/- diabetic), and also from anti-CCL17/22 or anti-CD25-injected diabetic mice that presented with accelerated wound healing and fewer regulatory T cells in the wound bed. Consequently, CCR4-/- diabetic mice also presented with alteration on T cells population in the wound and draining lymph nodes; on day 14, these mice also displayed an increase of collagen fiber deposition. Still, cytokine levels were decreased in the wounds of CCR4-/- diabetic mice on day 2. Our data suggest that the receptor CCR4 and regulatory T cells negatively affect wound healing in diabetic mice.
Asunto(s)
Quimiocina CCL17/antagonistas & inhibidores , Quimiocina CCL22/antagonistas & inhibidores , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Receptores CCR4/metabolismo , Cicatrización de Heridas/efectos de los fármacos , Aloxano/farmacología , Análisis de Varianza , Animales , Biopsia con Aguja , Quimiocina CCL17/farmacología , Quimiocina CCL22/farmacología , Quimiocinas/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Cicatrización de Heridas/fisiologíaRESUMEN
BACKGROUND: The numbers of IL-27-producing CD4(+) T cells and the concentration of soluble IL-27 have been found to be increased in tuberculous pleural effusion (TPE). The objective of the present study was to explore the mechanism by which IL-27(+)CD4(+) T cells are recruited into the pleural space, and to explore the impact of IL-27 on pleural mesothelial cells (PMCs). METHODS: The expression profiles of chemokine receptor (CCR) were determined by flow cytometry. The chemoattractant activity of chemokines CCL20 and CCL22 for IL-27(+)CD4(+) T cells in vitro was observed. Effects of IL-27 on wound healing, proliferation and apoptosis of PMCs were also investigated. RESULTS: IL-27(+)CD4(+) T cells in TPE expressed high level of CCR6, medium level of CCR4, and low levels of CCR2, CCR3, CCR5, CCR7, CCR10, and CXCR3. Recruitment of IL-27(+)CD4(+) T cells into TPE could be induced by pleural CCL20 and CCL22. By activating STAT3 signaling, IL-27 significantly improved wound healing and promoted proliferation of PMCs, and completely prevented apoptosis of PMCs induced by IFN-γ. CONCLUSIONS: After being recruited into pleural space by CCL20 or/and CCL22, these pleural IL-27-producing CD4(+) T cells may play important roles in tuberculosis immunity by affecting PMC functions.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Quimiotaxis de Leucocito/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Interleucina-27/farmacología , Tuberculosis Pleural/inmunología , Apoptosis/efectos de los fármacos , Linfocitos T CD4-Positivos/química , Linfocitos T CD4-Positivos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Quimiocina CCL20/farmacología , Quimiocina CCL22/farmacología , Humanos , Interferón gamma/farmacología , Interleucina-27/análisis , Pleura/citología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Tuberculosis Pleural/patología , Cicatrización de Heridas/efectos de los fármacosRESUMEN
The chemokine receptor CCR4 has at least two natural agonist ligands, MDC (CCL22) and TARC (CCL17) which bind to the same orthosteric site with a similar affinity. Both ligands are known to evoke chemotaxis of CCR4-bearing T cells and also elicit CCR4 receptor internalization. A series of small molecule allosteric antagonists have been described which displace the agonist ligand, and inhibit chemotaxis. The aim of this study was to determine which cellular coupling pathways are involved in internalization, and if antagonists binding to the CCR4 receptor could themselves evoke receptor internalization. CCL22 binding coupled CCR4 efficiently to ß-arrestin and stimulated GTPγS binding however CCL17 did not couple to ß-arrestin and only partially stimulated GTPγS binding. CCL22 potently induced internalization of almost all cell surface CCR4, while CCL17 showed only weak effects. We describe four small molecule antagonists that were demonstrated to bind to two distinct allosteric sites on the CCR4 receptor, and while both classes inhibited agonist ligand binding and chemotaxis, one of the allosteric sites also evoked receptor internalization. Furthermore, we also characterize an N-terminally truncated version of CCL22 which acts as a competitive antagonist at the orthosteric site, and surprisingly also evokes receptor internalization without demonstrating any agonist activity. Collectively this study demonstrates that orthosteric and allosteric antagonists of the CCR4 receptor are capable of evoking receptor internalization, providing a novel strategy for drug discovery against this class of target.
Asunto(s)
Quimiotaxis/fisiología , Endocitosis/fisiología , Receptores CCR4/antagonistas & inhibidores , Receptores CCR4/metabolismo , Regulación Alostérica/efectos de los fármacos , Regulación Alostérica/fisiología , Animales , Basófilos/efectos de los fármacos , Basófilos/metabolismo , Células CHO , Células Cultivadas , Quimiocina CCL17/farmacología , Quimiocina CCL22/farmacología , Quimiotaxis/efectos de los fármacos , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Endocitosis/efectos de los fármacos , HumanosRESUMEN
The hallmark of periodontal disease is the progressive destruction of gingival soft tissue and alveolar bone, which is initiated by inflammation in response to an invasive and persistent bacterial insult. In recent years, it has become apparent that this tissue destruction is associated with a decrease in local regulatory processes, including a decrease of forkhead box P3-expressing regulatory lymphocytes. Accordingly, we developed a controlled release system capable of generating a steady release of a known chemoattractant for regulatory lymphocytes, C-C motif chemokine ligand 22 (CCL22), composed of a degradable polymer with a proven track record of clinical translation, poly(lactic-co-glycolic) acid. We have previously shown that this sustained presentation of CCL22 from a point source effectively recruits regulatory T cells (Tregs) to the site of injection. Following administration of the Treg-recruiting formulation to the gingivae in murine experimental periodontitis, we observed increases in hallmark Treg-associated anti-inflammatory molecules, a decrease of proinflammatory cytokines, and a marked reduction in alveolar bone resorption. Furthermore, application of the Treg-recruiting formulation (fabricated with human CCL22) in ligature-induced periodontitis in beagle dogs leads to reduced clinical measures of inflammation and less alveolar bone loss under severe inflammatory conditions in the presence of a diverse periodontopathogen milieu.
Asunto(s)
Pérdida de Hueso Alveolar/inmunología , Pérdida de Hueso Alveolar/prevención & control , Quimiocina CCL22/farmacología , Sistemas de Liberación de Medicamentos/métodos , Periodontitis/complicaciones , Linfocitos T Reguladores/inmunología , Aggregatibacter actinomycetemcomitans/efectos de los fármacos , Pérdida de Hueso Alveolar/etiología , Animales , Quimiocina CCL22/administración & dosificación , Preparaciones de Acción Retardada/farmacología , Perros , Ácido Láctico , Ratones , Periodontitis/microbiología , Ácido Poliglicólico , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Porphyromonas gingivalis/efectos de los fármacosRESUMEN
CC chemokine receptor 4 (CCR4) has been implicated as a preferential marker for T helper type 2 (Th2) cells, and is believed to be involved in the pathology of allergic diseases by controlling Th2 cell trafficking into inflamed tissues. The objective of the study was to characterize the pharmacological properties of E0001-163, a novel CCR4 antagonist. E0001-163 was tested in both in vitro chemotaxis assays as well as in vivo mouse models of CCR4 ligand-induced air pouch and antigen-induced airway inflammation by utilizing in vitro-polarized Th2 cells. In vitro, E0001-163 inhibited migratory response of human Th2-polarized cells to CCL22, a CCR4 ligand, with an IC50 value of 11.9 nM. E0001-163 significantly suppressed CCL22-induced Th2 cell trafficking into mouse air pouch in a dose-dependent manner at doses of 3 and 10mg/kg, suggesting that E0001-163 has an inhibitory effect on CCR4-mediated T cell trafficking in vivo. In addition, E0001-163 partially decreased Th2 cell trafficking and the level of IL-4 in the lungs in Th2-tansferred and ovalbumin (OVA)-challenged mice. T cell trafficking involves multiple chemokine receptors both in acute and chronic phases, and our findings suggest that CCR4, together with other chemokine receptors, may be involved in Th2 cell trafficking under disease conditions.
Asunto(s)
Antialérgicos/farmacología , Neumonía/inmunología , Receptores CCR4/antagonistas & inhibidores , Sulfanilamidas/farmacología , Células Th2/efectos de los fármacos , Traslado Adoptivo , Animales , Antialérgicos/farmacocinética , Antígenos/inmunología , Línea Celular , Movimiento Celular/efectos de los fármacos , Quimiocina CCL22/farmacología , Células HEK293 , Humanos , Ligandos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Ovalbúmina/inmunología , Receptores CCR4/inmunología , Bazo/citología , Sulfanilamidas/farmacocinética , Células Th2/inmunología , Células Th2/fisiologíaAsunto(s)
Biomimética/métodos , Movimiento Celular/efectos de los fármacos , Quimiocina CCL22/metabolismo , Quimiocina CCL22/farmacología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/efectos de los fármacos , Animales , Movimiento Celular/inmunología , Quimiocina CCL22/administración & dosificación , Preparaciones de Acción Retardada , Portadores de Fármacos/química , Femenino , Inmunomodulación/efectos de los fármacos , Ratones , Microesferas , Linfocitos T Reguladores/inmunologíaRESUMEN
BACKGROUND: CD4(+)CD25(+) regulatory T cells (Tregs), a heterogeneous population, were enrichment in tumor mass and played an important role in modulating anti-tumor immunity. Recently, we reported a Treg subset, CCR6(+) Tregs but not CCR6(-)Tregs, were enriched in tumor mass and closely related to poor prognosis of breast cancer patients. However, the underlying mechanism remains elusive. Here, we carefully evaluate the enrichment of CCR6(+)Tregs in tumor mass during progression of breast cancer and explore its possible mechanism. METHODOLOGY/PRINCIPAL FINDINGS: The frequency of CCR6(+)Tregs in tumor infiltrating lymphocytes (TILs ) was analyzed at early stage and at late stage of tumor in a murine breast cancer model by FACS respectively. The expansion of CCR6(+)Tregs and their CCR6(-) counterpart in tumor mass were determined by BrdU incorporation assay. The effect and its possible mechanism of tumor-resident antigen presenting cells (APCs) on the proliferation of CCR6(+)Tregs also were evaluated. The role of local expansion of CCR6(+)Tregs in their enrichment and suppression in vivo also was evaluated in adoptive cell transfer assay. We found that the prior enrichment of CCR6(+)Tregs but not CCR6(-)Tregs in tumor mass during progression of murine breast cancer, which was dependent on the dominant proliferation of CCR6(+) Tregs in situ. Further study demonstrated that tumor-resident DCs triggered the proliferation of CCR6(+)Treg cells in TGF-ß dependent manner. Adoptive transfer of CCR6(+)Tregs was found to potently inhibit the function of CD8(+)T cells in vivo, which was dependent on their proliferation and subsequently enrichment in tumor mass. CONCLUSIONS/SIGNIFICANCE: Our finding suggested that CCR6(+) Tregs, a distinct subset of Tregs, exert its predominant suppressive role in tumor immunity through prior in situ expansion, which might ultimately provide helpful thoughts for the designing of Treg-based immunotherapy for tumor in the future.
Asunto(s)
Receptores CCR6/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quimiocina CCL17/farmacología , Quimiocina CCL20/farmacología , Quimiocina CCL22/farmacología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Receptores CCR6/genéticaRESUMEN
CC Chemokine ligand 22 (Ccl22) is a selective, high affinity ligand at the CC chemokine receptor 4 (Ccr4). We have identified cDNAs encoding both ligand and receptor of the Ccl22-Ccr4 pair in cDNA libraries of the anterior hypothalamus/pre-optic area (AH/POA) by PCR. The AH/POA is the key brain region where endogenous pyrogens have been shown to act on warm sensitive neurons to affect thermogenesis in brown adipose tissue (BAT) and other thermogenically responsive tissues. We show that functional Ccr4 receptors are present in the AH/POA neurons as injection of Ccl22 into the POA but not to other hypothalamic nuclei induces an increase in core body temperature as measured by radiotelemetry. Indomethacin (5 mg/kg s.c) pre-treatment markedly reduced the hyperthermia evoked by POA injection of Ccl22 (10 ng/0.5 ul) and thus suggests that this hyperthermia is mediated through cyclooxygenase activation and thus likely through the formation and action of the pyrogen prostaglandin E2. The temperature elevation involves a decrease in the respiratory exchange ratio and increased activation of the brown adipose tissue as demonstrated by ¹8F-FDG-PET imaging. We describe a novel role to the ligand Ccl22 and its receptor Ccr4 in the anterior hypothalamus in temperature regulation that depends on the synthesis of the endogenous pyrogen, prostaglandin E2.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Quimiocina CCL22/genética , Fiebre/fisiopatología , Hipotálamo Anterior/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/farmacología , Temperatura Corporal/efectos de los fármacos , Quimiocina CCL22/metabolismo , Quimiocina CCL22/farmacología , Dinoprostona/metabolismo , Femenino , Fiebre/inducido químicamente , Fiebre/prevención & control , Expresión Génica , Hipotálamo Anterior/efectos de los fármacos , Indometacina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Tomografía de Emisión de Positrones , Área Preóptica/efectos de los fármacos , Área Preóptica/metabolismo , Pirógenos/metabolismo , Pirógenos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores CCR4/genética , Receptores CCR4/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Telemetría , Tomografía Computarizada por Rayos XRESUMEN
Cutaneous T-cell lymphoma (CTCL) encompasses leukemic variants (L-CTCL) such as Sézary syndrome (SS) and primarily cutaneous variants such as mycosis fungoides (MF). To clarify the relationship between these clinically disparate presentations, we studied the phenotype of T cells from L-CTCL and MF. Clonal malignant T cells from the blood of L-CTCL patients universally coexpressed the lymph node homing molecules CCR7 and L-selectin as well as the differentiation marker CD27, a phenotype consistent with central memory T cells. CCR4 was also universally expressed at high levels, and there was variable expression of other skin addressins (CCR6, CCR10, and CLA). In contrast, T cells isolated from MF skin lesions lacked CCR7/L-selectin and CD27 but strongly expressed CCR4 and CLA, a phenotype suggestive of skin resident effector memory T cells. Our results suggest that SS is a malignancy of central memory T cells and MF is a malignancy of skin resident effector memory T cells.
Asunto(s)
Linfocitos T CD4-Positivos/patología , Micosis Fungoide/patología , Síndrome de Sézary/patología , Neoplasias Cutáneas/patología , Subgrupos de Linfocitos T/patología , Antígenos CD/biosíntesis , Antígenos CD/genética , Antígenos de Neoplasias/biosíntesis , Antígenos de Neoplasias/genética , Linfocitos T CD4-Positivos/química , Quimiocina CCL21/farmacología , Quimiocina CCL22/farmacología , Quimiotaxis/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Reordenamiento Génico de la Cadena beta de los Receptores de Antígenos de los Linfocitos T , Humanos , Memoria Inmunológica , Selectina L/biosíntesis , Selectina L/genética , Ganglios Linfáticos/inmunología , Células Madre Neoplásicas/química , Células Madre Neoplásicas/patología , Fenotipo , Receptores CCR7/biosíntesis , Receptores CCR7/genética , Piel/citología , Piel/inmunología , Subgrupos de Linfocitos T/químicaRESUMEN
PURPOSE: The aim of this study was to explore the presence of the chemokines CCL22 and CCL17 in malignant pleural effusion, and the chemoattractant activity of these chemokines on CD4-positive CD25-positive Foxp3-positive regulatory T cells infiltrating into the pleural space. EXPERIMENTAL DESIGN: The concentrations of CCL22 and CCL17 in both pleural effusions and sera from 33 patients with lung cancer were determined. Flow cytometry was done to determine T lymphocyte subsets in cell pellets of pleural effusion. Pleural cells were analyzed for the expression of CCL22 and CCL17. The chemoattractant activity of CCL22 for regulatory T cells in vitro and in vivo was also observed. RESULTS: The concentration of CCL22 in malignant pleural effusion was significantly higher than that in the corresponding serum. Pleural fluid from lung cancer patients was chemotactic for regulatory T cells, and this activity was partly blocked by an anti-CCL22, but not by an anti-CCL17 antibody. Intrapleural administration of CCL22 of patients produced a marked progressive influx of regulatory T cells into pleural space. CONCLUSIONS: Compared with serum, CCL22 seemed to be increased in malignant pleural effusion, and could directly induce regulatory T cell infiltration into the pleural space in patients with malignant effusion.