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1.
J Hepatol ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31813573

RESUMO

BACKGROUND & AIMS: C-C motif chemokine receptor 2 (CCR2) has been recognized as a promising target for the treatment of liver fibrosis. PC3-secreted microprotein (PSMP)/microseminoprotein (MSMP) is a novel chemotactic cytokine and its receptor is CCR2. In the present study we investigated the expression and role of PSMP in liver fibrosis/cirrhosis. METHODS: PSMP expression was studied in patients with fibrosis/cirrhosis and in 3 murine models of liver fibrosis, including mice treated with carbon tetrachloride (CCl4), bile-duct ligation, or a 5-diethoxycarbonyl-1,4-dihydrocollidine diet. The role of PSMP was evaluated in Psmp-/- mice and after treatment with a PSMP antibody in wild-type mice. The direct effects of PSMP on macrophages and hepatic stellate cells were studied in vitro. RESULTS: In this study, we found that PSMP was highly expressed in fibrotic/cirrhotic tissues from patients with different etiologies of liver disease and in the 3 experimental mouse models of fibrosis. Damage-associated molecular pattern molecules HMGB-1 and IL-33 induced hepatocytes to produce PSMP. PSMP deficiency resulted in a marked amelioration of hepatic injury and fibrosis. In CCl4-induced hepatic injury, the infiltration of macrophages and CCR2+ monocytes into the liver was significantly decreased in Psmp-/- mice. Consistent with the decreased levels of intrahepatic macrophages, proinflammatory cytokines were significantly reduced. Moreover, adeno-associated virus-8 vectors successfully overexpressing human PSMP in Psmp-/- mouse livers could reverse the attenuation of liver injury and fibrosis induced by CCl4 in a CCR2-dependent manner. Treatment with a specific PSMP-neutralizing antibody, 3D5, prevented liver injury and fibrosis induced by CCl4 in mice. At the cellular level, PSMP directly promoted M1 polarization of macrophages and activation of LX-2 cells. CONCLUSION: PSMP enhances liver fibrosis through its receptor, CCR2. PSMP is a potentially attractive therapeutic target for the treatment of patients with liver fibrosis. LAY SUMMARY: Our present study identifies the essential role of the protein PSMP for the development and progression of liver fibrosis in humans and mice. PSMP promotes liver fibrosis through inflammatory macrophage infiltration, polarization and production of proinflammatory cytokines, as well as direct activation of hepatic stellate cells via its receptor CCR2. A PSMP antibody can significantly reduce liver fibrosis development in vivo. These findings indicate that PSMP is a potential therapeutic target and its antibody is a potential therapeutic agent for the treatment of liver fibrosis.

2.
ACS Omega ; 4(23): 20275-20284, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31815230

RESUMO

Polyphosphazene microspheres were fabricated by ultrasonic-assisted precipitation polymerization using 4,4'-(hexafluoroisopropylidene)diphenol, 4,4'-sulfonyldiphenol, 4,4-(9-fluorenylidene)diphenol, and phenolphthalein to obtain poly[4,4'-(hexafluoroisopropylidene)diphenol]phosphazene (PZAF), poly(4,4'- sulfonyldiphenol)phosphazene (PZS), poly[4,4'-(9-fluorenylidene)diphenol]phosphazene, and poly(phenolphthalein)phosphazene (PZPT) and were incorporated into polybenzoxazines (PBa) to obtain corresponding PZAF/PBa, PZS/PBa, fluorenyl polyphosphazene (PZFP)/PBa, and PZPT/PBa composites. Addition of 5 wt % of PZAF, PZS, PZFP, and PZPT microspheres improved the thermal stability and fire retardancy of PBa resin significantly. Notably, addition of PBa with 5% PZAF led to a 62.5% decrease in the peak heat release rate and 49.3% reduction in total heat release. The role of microspheres in the gas-phase flame-retardancy mechanism in the PBa matrix was studied. Dynamic mechanical analysis results demonstrated that the T g of PBa flame-retardant composites was still around 210 °C compared to 221 °C of pure PBa. Hence, the synthesized PBa composites had potential applications as high flame-retardancy materials.

3.
NPJ Breast Cancer ; 5: 20, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31372496

RESUMO

TP53 mutations are common in breast cancer and are typically associated with more aggressive tumor characteristics, but little is known about the clinicopathological and epidemiological relevance of p53 protein expression, a TP53 mutation surrogate, in breast cancer subtypes. In this study of 7226 Chinese women with invasive breast cancer, we defined breast cancer subtypes using immunohistochemical (IHC) measures of hormone receptors and HER2 in conjunction with histologic grade. p53 expression status was then used to further stratify subtypes into p53-positive and p53-negative. Odds ratios (ORs) and 95% confidence intervals (CIs) in case-only logistic regression analyses were used to examine heterogeneity across different subtypes. The frequency of p53 protein expression varied by breast cancer subtype, being lowest in the luminal A-like and highest in the triple-negative and HER2-enriched subtypes (P-value < 0.01). In luminal A-like and B-like/HER2-negative subtypes, p53 positivity was associated with early-onset tumors, high grade, high proliferative index, and basal marker (CK5/6 and EGFR) expression. Further, compared with luminal A-like/p53-negative patients, A-like/p53-positive patients were more likely to be parous [adjusted OR parous vs. nulliparous = 2.67 (1.60, 4.51); P-value < 0.01] and to have breastfed [adjusted OR ever vs. never = 1.38 (1.03, 1.85); P-value = 0.03]. p53 positivity was not associated with examined clinical and risk factors in other tumor subtypes. Overall, these findings suggest that p53 expression, which is readily available in many settings, can be used to identify phenotypes of luminal A-like breast cancer with distinct clinical and epidemiological implications.

4.
Breast Cancer Res Treat ; 177(2): 527-536, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31254158

RESUMO

PURPOSE: Mammographic density (MD) is a strong risk factor for breast cancer, yet its relationship with tumor characteristics is not well established, particularly in Asian populations. METHODS: MD was assessed from a total of 2001 Chinese breast cancer patients using Breast Imaging Reporting and Data System (BI-RADS) categories. Molecular subtypes were defined using immunohistochemical status on ER, PR, HER2, and Ki-67, as well as tumor grade. Multinomial logistic regression was used to test associations between MD and molecular subtype (luminal A = reference) adjusting for age, body mass index (BMI), menopausal status, parity, and nodal status. RESULTS: The mean age at diagnosis was 51.7 years (SD = 10.7) and the average BMI was 24.7 kg/m2 (SD = 3.8). The distribution of BI-RADS categories was 7.4% A = almost entirely fat, 24.2% B = scattered fibroglandular dense, 49.4% C = heterogeneously dense, and 19.0% D = extremely dense. Compared to women with BI-RADS = A/B, women with BI-RADS = D were more likely to have HER2-enriched tumors (OR = 1.81, 95% CI 1.08-3.06, p = 0.03), regardless of menopausal status. The association was only observed in women with normal (< 25 kg/m2) BMI (OR = 2.43, 95% CI 1.24-4.76, p < 0.01), but not among overweight/obese women (OR: 0.98, 95% CI 0.38-2.52, p = 0.96). CONCLUSIONS: Among Chinese women with normal BMI, higher breast density was associated with HER2-enriched tumors. The results may partially explain the higher proportion of HER2+ tumors previously reported in Asian women.


Assuntos
Densidade da Mama , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Adulto , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/etiologia , China/epidemiologia , Feminino , Humanos , Imuno-Histoquímica , Mamografia , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Razão de Chances , Fatores de Risco
5.
J Immunother ; 42(6): 215-220, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31145232

RESUMO

The effect of chemotherapy on programmed cell death-ligand 1 (PD-L1) expression has been previously studied in lung cancer, while the results remain controversial. The aim of this study was to investigate the variation of PD-L1 expression after neoadjuvant chemotherapy and explore the association between chemotherapy response, prognosis and the variation of PD-L1 expression in lung cancer patients. A total of 63 lung cancer patients who received platinum-based neoadjuvant chemotherapy and subsequently underwent surgical resection were selected. PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) was assessed by immunohistochemistry using 22C3 monoclonal antibody in these 63 matched lung cancer specimens before and after neoadjuvant chemotherapy. The positivity of PD-L1 on TC changed from 17.5% to 39.7% after neoadjuvant chemotherapy and the positivity of PD-L1 on IC changed from 19.0% to 71.4% after neoadjuvant chemotherapy. The elevation of PD-L1 expression on TC after neoadjuvant chemotherapy was more frequently observed in patients achieving stable disease or progressive disease than in patients achieving partial response (P=0.026). Patients with elevated PD-L1 expression on TC after neoadjuvant chemotherapy showed a trend to have a shorter progression-free survival than patients without elevated PD-L1 expression on TC, although the difference was not statistically significant in multivariate analysis (hazard ratio=2.38, 95% confidence interval=0.99-5.73, P=0.053). PD-L1 expression can be elevated by chemotherapy in lung cancer. Furthermore, elevation of PD-L1 expression on TC after neoadjuvant chemotherapy was associated with reduced chemotherapy response and inferior progression-free survival in patients with lung cancer.

6.
Thorac Cancer ; 10(2): 175-182, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30536734

RESUMO

BACKGROUND: PD-L1 expression in tumor cells has been associated with the efficacy of immune checkpoint inhibitors in non-small cell lung cancer (NSCLC). The aim of this study was to explore correlations between smoking, genetic profiles, patient outcomes, and PD-L1 expression in NSCLC. METHODS: PD-L1 expression was evaluated in 241 surgically resected specimens by immunostaining and 50% was set as the cutoff value. RESULTS: Of the 241 tumors analyzed, a PD-L1 tumor proportion score (TPS) of ≥ 50% was detected in 35 cases (14.5%) and a TPS of < 50% in 206 cases (85.5%). A PD-L1 TPS ≥ 50% was significantly associated with smoking and EGFR wild-type status (P < 0.001 and P = 0.039, respectively). Detailed assessment of smoking variables showed that total smoking duration was a predictor of a PD-L1 TPS ≥ 50% (P = 0.001). Univariate and multivariate survival analyses revealed that patients with a PD-L1 TPS ≥ 50% had poorer disease-free and overall survival than those with a PD-L1 TPS < 50% (P = 0.001 and P < 0.001, respectively). CONCLUSION: The incidence of a PD-L1 TPS ≥ 50% was significantly higher in smoking and EGFR wild-type NSCLC patients, particularly in long-term smokers. A PD-L1 TPS of ≥ 50% was an independent adverse prognostic factor for survival in patients with NSCLC.

7.
Int J Cancer ; 145(1): 70-77, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30561789

RESUMO

Extensive mammographic density (MD), a well-established breast cancer risk factor, is a radiological representation of stromal and epithelial breast tissue content. In studies conducted predominantly among Caucasian women, histologic measures of reduced terminal duct lobular unit (TDLU) involution have been correlated with extensive MD, but independently associated with breast cancer risk. We therefore examined associations between TDLU measures and MD among Chinese women, a low-risk population but with high prevalence of dense breasts. Diagnostic pre-treatment digital mammograms were obtained from 144 breast cancer cases at a tertiary hospital in Beijing and scored using the Breast Imaging Reporting and Data System (BI-RADS) density classification. TDLU features were assessed using three standardized measures (count/100 mm2 , span [µm], and acini count/TDLU) in benign tissues. Associations between each of TDLU measures and MD were examined using generalized linear models for TDLU count and span and polytomous logistic regression for acini count with adjustment for potential confounders stratified by age. Among women ≥50 years, 63% had dense breasts; cases with dense breasts (BI-RADS, c-d) had greater TDLU count (21.1 [SE = 2.70] vs. 9.0 [SE = 1.83]; p = 0.0004), longer span (480.6 µm [SE = 24.6] vs. 393.8 µm [SE = 31.8]; p = 0.03), and greater acini count (ORtrend = 16.1; 95%CI = 4.08-63.1; ptrend < 0.0001) compared to those with non-dense breasts (BI-RADS, a-b). Among women <50 years, 91% had dense breasts, precluding our ability to detect associations. Our findings are consistent with previously reported associations between extensive MD and reduced TDLU involution, supporting the hypothesis that breast cancer risk associated with extensive MD may be related to the amount of "at-risk" epithelium.


Assuntos
Neoplasias da Mama/patologia , Glândulas Mamárias Humanas/patologia , Adulto , Fatores Etários , Idoso , Grupo com Ancestrais do Continente Asiático , Densidade da Mama , Neoplasias da Mama/diagnóstico por imagem , Feminino , Humanos , Glândulas Mamárias Humanas/diagnóstico por imagem , Mamografia , Pessoa de Meia-Idade , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/patologia , Adulto Jovem
8.
Sci Rep ; 7(1): 5107, 2017 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-28698550

RESUMO

Monocytes/macrophages have been found to be an important component of colitis. However, the key chemokine that initiates the CCR2+ monocytes migration from circulation to colitis tissue remains to be undiscovered. PC3-secreted microprotein (PSMP) is a novel chemokine whose receptor is CCR2. The physiological and pathological functions of PSMP have not yet been reported. In this study, PSMP was found to be expressed in colitis and colonic tumor tissues from patients and significantly up-regulated in mouse DSS-induced colitis tissues. PSMP overexpression in the colon aggravated the DSS-induced colitis and the anti-PSMP neutralizing antibody mollified the colitis by reducing macrophage infiltration and inhibiting the expression of IL-6, TNF-α and CCL2. Furthermore, we demonstrated that lipopolysaccharide and muramyl dipeptide induced PSMP expression in the colonic epithelial cells. PSMP was up-regulated in the initial stage prior to IL-6, TNF-α and CCL2 up-regulated expression in DSS colitis and promoted the M1 macrophages to produce CCL2. PSMP chemo-attracted Ly6Chi monocytes in a CCR2 dependent manner via in situ chemotaxis and adoptive transfer assays. Our data identify PSMP as a key molecule in ulcerative colitis, which provides a novel mechanism of monocyte/macrophage migration that affects gut innate immunity and makes PSMP a potential target for controlling colitis.


Assuntos
Colite/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Secretadas pela Próstata/metabolismo , Receptores CCR2/metabolismo , Animais , Movimento Celular , Quimiocina CCL2/metabolismo , Colite/induzido quimicamente , Sulfato de Dextrana , Modelos Animais de Doenças , Humanos , Interleucina-6/metabolismo , Masculino , Camundongos , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
9.
Breast Cancer Res ; 19(1): 61, 2017 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-28545469

RESUMO

BACKGROUND: Terminal duct lobular unit (TDLU) involution is a physiological process of breast tissue aging characterized by a reduction in the epithelial component. In studies of women with benign breast disease, researchers have found that age-matched women with lower levels of TDLU involution are at increased risk of developing breast cancer. We previously showed that breast cancer cases with core basal phenotype (CBP; estrogen receptor negative [ER-], progesterone receptor-negative [PR-], human epidermal growth factor receptor 2-negative [HER2-], cytokeratins (CK 5 or CK5/6)-positive [CK5/6+] and/or epidermal growth factor receptor-positive [EGFR+]) tumors had significantly reduced TDLU involution compared with cases with luminal A (ER+ and/or PR+, HER2-, CK5/6-, EGFR-) tumors from a population-based case-control study in Poland. We evaluated the association of TDLU involution with tumor subtypes in an independent population of women in China, where the breast cancer incidence rate, prevalence of known risk factors, and mammographic breast density are thought to be markedly different from those of Polish women. METHODS: We performed morphometric assessment of TDLUs by using three reproducible semiquantitative measures that inversely correlate with TDLU involution (TDLU count/100 mm2, TDLU span in micrometer, and acini count/TDLU) by examining benign tissue blocks from 254 age-matched luminal A and 250 triple-negative (TN; ER-, PR-, HER2-, including 125 CBP) breast cancer cases treated in a tertiary hospital in Beijing, China. RESULTS: Overall, we found that TN and particularly CBP cases tended to have greater TDLU measures (less involution) than luminal A cases in logistic regression models accounting for age, body mass index, parity, and tumor grade. The strongest association was observed for tertiles of acini count among younger women (aged <50 years) (CBP vs. luminal A; ORtrend 2.11, 95% CI 1.22-3.67, P = 0.008). CONCLUSIONS: These data extend previous findings that TN/CBP breast cancers are associated with reduced TDLU involution in surrounding breast parenchyma compared with luminal A cases among Chinese women, providing further support for differences in the pathogenesis of these tumor subtypes.


Assuntos
Neoplasias da Mama/patologia , Glândulas Mamárias Humanas/patologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Fatores Etários , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/metabolismo , China , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prevalência , Fatores de Risco , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto Jovem
10.
J Immunol ; 192(4): 1878-86, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24442440

RESUMO

PC3-secreted microprotein (PSMP) or microseminoprotein is a newly discovered secreted protein whose function is currently unknown. In this study, PSMP was found to possess chemotactic ability toward monocytes and lymphocytes, and its functional receptor was identified as CCR2B. PSMP was identified as a chemoattractant protein from a PBMC chemoattractant platform screen that we established. The mature secreted PSMP was able to chemoattract human peripheral blood monocytes, PBLs, and CCR2B-expressing THP-1 cells, but not peripheral blood neutrophils, even though it does not contain the classical structure of chemokines. CCR2B was identified as one receptor for PSMP-mediated chemotaxis by screening HEK293 cells that transiently expressed classical chemokine receptors; results obtained from the chemotaxis, calcium flux, receptor internalization, and radioligand-binding assays all confirmed this finding. To further identify the major function of PSMP, we analyzed its expression profile in tissues. PSMP is highly expressed in benign prostatic hyperplasia and in some prostate cancers, and can also be detected in breast tumor tissue. In response to PSMP stimulation, phosphorylated ERK levels downstream of CCR2B signaling were upregulated in the PC3 cell line. Taken together, our data collectively suggest that PSMP is a chemoattractant protein acting as a novel CCR2 ligand that may influence inflammation and cancer development.


Assuntos
Fatores Quimiotáticos/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores CCR2/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Expressão Gênica , Células HEK293 , Humanos , Inflamação/metabolismo , Ligantes , Linfócitos/metabolismo , Masculino , Monócitos/metabolismo , Neutrófilos/metabolismo , Fosforilação , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/metabolismo , Ligação Proteica
11.
Zhonghua Bing Li Xue Za Zhi ; 43(12): 794-8, 2014 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-25623974

RESUMO

OBJECTIVE: To study the prevalence of the BRAF V600E mutation in papillary thyroid carcinoma (PTC) and its association with clinicopathologic features. METHODS: Two hundred and ninety-two patients with primary PTC encountered during the period from December 2010 to December 2012 and underwent surgery in Cancer Hospital, Chinese Academy of Medical Science were enrolled into the study. Polymerase chain reaction was used to amplify exon 15 of the BRAF gene from paraffin-embedded thyroid tumor specimens, followed by direct sequencing to detect the BRAF V600E mutation. Statistical analysis was performed with SPSS 16.0 for Windows. Association between BRAF mutation and clinicopathologic parameters was tested with the χ(2) test or Fisher exact test as appropriate. RESULTS: There were 87 males and 205 females in the cohort. The age of patients ranged from 13 to 84 years (mean = 43.1 years). BRAF V600E mutation was found in 190 cases (65.1%). The presence of BRAF V600E mutation correlated with age at diagnosis (older than 45 years), tumor volume (larger than 1 cm), extrathyroidal extension, classic type/tall-cell variant and advanced disease stage (P < 0.05). BRAF V600E mutation did not correlate significantly with gender, multicentricity, lymph node metastasis or anatomic location (P > 0.05). CONCLUSION: BRAF V600E mutation is associated with high-risk clinicopathologic characteristics in patients with PTC. The BRAF V600E mutation may be a potential prognostic factor in PTC patients.


Assuntos
Carcinoma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Carcinoma/patologia , Carcinoma Papilar , Éxons , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologia
12.
Int Arch Allergy Immunol ; 159(3): 297-305, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22739408

RESUMO

BACKGROUND: CCR4 is highly expressed on Th2 cells. These cells play an important role in acute inflammatory responses, including those involved in allergic rhinitis. We determined whether disrupting the CCR4 ligand interaction with CCR4 antagonist could alleviate allergic rhinitis in a mouse model. METHODS: BALB/c mice were sensitized with ovalbumin and alum by intraperitoneal injection and challenged with intranasally administered ovalbumin. Compound 22, which has been reported as a novel small-molecule antagonist of CCR4, was also administered intranasally. In addition, budesonide, an efficient glucocorticoid, was used as a positive control. The effects of compound 22 were quantified by multiple parameters of allergic responses in both nasal and pulmonary tissues. RESULTS: Compound 22 significantly improved symptoms of allergic rhinitis and suppressed levels of total IgE of serum. It dramatically reduced the levels of IL-4 in bronchoalveolar lavage fluid and also decreased the number of inflammatory cells in the fluid. The infiltration of inflammatory cells, especially eosinophils, was markedly reduced in the nasal and pulmonary tissues. The number of IL-4+ cells was also significantly reduced in these tissues. Moreover, the numbers of Foxp3+ cells and IL-17+ cells were reduced, though not to a statistically significant degree. CONCLUSIONS: In our research, CCR4 antagonists such as compound 22 were proven for the first time to alleviate murine allergic rhinitis when administered nasally. CCR4 antagonists may have therapeutic potential for the treatment of allergic rhinitis.


Assuntos
Fatores Imunológicos/farmacologia , Receptores CCR4/antagonistas & inibidores , Rinite Alérgica Perene/tratamento farmacológico , Células Th2/efeitos dos fármacos , Administração Intranasal , Compostos de Alúmen , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Budesonida/farmacologia , Quimiotaxia/efeitos dos fármacos , Quimiotaxia/imunologia , Modelos Animais de Doenças , Feminino , Glucocorticoides/farmacologia , Células HEK293 , Humanos , Imunização , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interleucina-4/sangue , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Ovalbumina , Receptores CCR4/imunologia , Rinite Alérgica Perene/induzido quimicamente , Rinite Alérgica Perene/imunologia , Células Th2/imunologia
13.
Int Immunopharmacol ; 11(12): 2188-93, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22001899

RESUMO

Human chemokine-like factor (CKLF1) is a human cytokine that exhibits chemotactic activities on a wide spectrum of leukocytes. One of CKLF1's C-terminal peptides, C19, exerts inhibitory effects on chemotaxis mediated by mouse Ccr3 and Ccr4 and human CCR3 and CCR4. Mouse models of asthma show that C19 can also inhibit the Th2 response. CCR3 and CCR4 are chemokine receptors important to allergic rhinitis, a condition whose pathogenesis is similar to that of asthma. Here, we established a mouse model of allergic rhinitis by repetitive sensitization and intranasal challenge with OVA and assessed whether C19 has therapeutic effects on this model. In this study, both intranasal and intraperitoneal administration of C19 reduced allergic symptoms such as sneezing and rubbing and serum concentration of IgE. C19 showed a strong ability to suppress eosinophil accumulation in nasal mucosa and lung tissues. C19 was able to suppress the Th2 cytokine IL-4 without augmenting the Th1 cytokine IFN-γ in BAL and IL-4(+) cells in the local nasal tissue. In terms of symptom amelioration, IgE reduction, and eosinophilia suppression, C19 was found to be as effective against allergic rhinitis as Budesonide. Moreover, intranasal treatment has a stronger therapeutic effect than other types of administration, and it may be more convenient and safe. For these reasons, C19 may have potential in the treatment of allergic rhinitis.


Assuntos
Anti-Inflamatórios/uso terapêutico , Budesonida/uso terapêutico , Proteínas de Membrana/imunologia , Peptídeos/uso terapêutico , Proteínas Repressoras/imunologia , Rinite Alérgica Perene/tratamento farmacológico , Administração Intranasal , Animais , Anti-Inflamatórios/administração & dosagem , Líquido da Lavagem Broncoalveolar/química , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Feminino , Imunoglobulina E/sangue , Interferon gama/análise , Interleucina-4/imunologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Proteínas com Domínio MARVEL , Camundongos , Camundongos Endogâmicos BALB C , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/patologia , Ovalbumina/administração & dosagem , Peptídeos/administração & dosagem , Rinite Alérgica Perene/induzido quimicamente , Rinite Alérgica Perene/patologia , Espirro/efeitos dos fármacos
14.
Biochem Biophys Res Commun ; 409(2): 356-61, 2011 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-21605546

RESUMO

CKLF1, a human cytokine that is a functional ligand for CCR4, is upregulated in various inflammation and autoimmune diseases. CKLF1 contains at least two secreted forms, the C-terminal peptides C19 and C27. Chemically synthesized C19 and C27 can interact with CCR4 and attenuate allergic inflammation. In this study, we found C19 and C27 could inhibit SDF-1-induced CXCR4-mediated chemotaxis and promote CXCR4 internalization. The inhibitory effect was due to desensitization of CXCR4, which was mediated by CCR4. Further experiments confirmed that CXCR4 desensitization required activation of PI3K/PKC pathway. Altogether our data elucidate the mechanism of C19- and C27-induced CXCR4 desensitization.


Assuntos
Quimiocinas/imunologia , Quimiotaxia/imunologia , Dessensibilização Imunológica , Hipersensibilidade/imunologia , Peptídeos/imunologia , Receptores CCR4/imunologia , Receptores CXCR4/imunologia , Quimiocina CXCL12/imunologia , Quimiocinas/química , Quimiocinas/farmacologia , Quimiotaxia/efeitos dos fármacos , Células HeLa , Humanos , Células Jurkat , Proteínas com Domínio MARVEL , Peptídeos/química , Peptídeos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Quinase C/metabolismo
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