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1.
Chem Pharm Bull (Tokyo) ; 68(1): 91-95, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902904

RESUMO

Magnolia Flower is a crude drug used for the treatment of headaches, toothaches, and nasal congestion. Here, we focused on Magnolia kobus, one of the botanical origins of Magnolia Flower, and collected the flower parts at different growth stages to compare chemical compositions and investigate potential inhibitory activities against interleukin-2 (IL-2) production in murine splenic T cells. After determining the structures, we examined the inhibitory effects of the constituents of the bud, the medicinal part of the crude drug, against IL-2 production. We first extracted the flower parts of M. kobus from the bud to fallen bloom stages and analysed the chemical compositions to identify the constituents characteristic to the buds. We found that the inhibitory activity of the buds against IL-2 production was more potent than that of the blooms. We isolated two known compounds, tiliroside (1) and syringin (2), characteristic to the buds from the methanol (MeOH) extract of Magnolia Flower. Moreover, we examined the inhibitory activities of both compounds against IL-2 production and found that tiliroside (1) but not syringin (2), showed strong inhibitory activity against IL-2 production and inhibited its mRNA expression. Thus, our strategy to examine the relationship between chemical compositions and biological activities during plant maturation could not only contribute to the scientific evaluation of medicinal parts of crude drugs but also assist in identifying biologically active constituents that have not yet been reported.


Assuntos
Interleucina-2/metabolismo , Magnolia/química , Extratos Vegetais/química , Animais , Linhagem Celular , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Flores/química , Flores/metabolismo , Glucosídeos/química , Glucosídeos/isolamento & purificação , Glucosídeos/farmacologia , Interleucina-2/genética , Magnolia/metabolismo , Camundongos , Fenilpropionatos/química , Fenilpropionatos/isolamento & purificação , Fenilpropionatos/farmacologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
2.
Anticancer Res ; 39(9): 4933-4940, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519598

RESUMO

BACKGROUND: Interleukin 2 (IL2) is a significant factor activating T-cell-mediated immune response by stimulation of natural killer cells, T-cells and in development of regulatory T (Treg) cells. Recent studies have that IL2 participates in cancer development by modifying the local immune response. Based on the suggested role of the single nucleotide polymorphisms (SNPs) rs2069762, rs6822844 and rs11938795 of IL2 in the pathogenesis of certain diseases, the relationship of these SNPs with clinicopathological variables and their possible implication for prognosis and disease outcome were evaluated in a cohort of Swedish patients with colorectal cancer (CRC). MATERIALS AND METHODS: TaqMan SNP genotype assays based on polymerase chain reaction were used for analysis of the IL2 SNPs in 467 patients with CRC and 467 healthy controls. Expression analysis of IL2 in plasma and CRC tissue was also performed. RESULTS: The allelic variants T in rs11938795 and G in rs6822844 were significantly associated with a higher risk of CRC. Kaplan-Meier analysis showed that cancer-specific survival was worse for individuals with C allele for rs2069762 with stage II CRC and with T allele for rs6822844 with stage III CRC. CONCLUSION: SNPs rs2069762, rs6822844 and rs11938795 of the IL2 gene may be helpful as prognostic biomarkers in the follow-up and management of the patients.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Variação Genética , Interleucina-2/genética , Adulto , Idoso , Alelos , Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/imunologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Imunomodulação , Interleucina-2/sangue , Interleucina-2/metabolismo , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Prognóstico , Medição de Risco
3.
BMC Res Notes ; 12(1): 496, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399137

RESUMO

OBJECTIVE: We recently reported that curcumin supplementation in a metabolically (i.e., Western diet [WD]) and chemically (i.e., CCl4) induced female rat model of non-alcoholic steatohepatitis (NASH) was associated with lower liver pathology scores and molecular markers of inflammation. This occurred when curcumin was given during induction of disease (preventative arm; 8-week WD with or without curcumin [8WD + C vs. 8WD]) as well as when given after disease development (treatment arm; 12-week WD with or without curcumin during weeks 9-12 [12WD + C vs. 12WD]). Herein, we sought to extend our findings from that study by determining the effects of curcumin supplementation on cytokine/chemokine expression in serum collected from these same rats. RESULTS: 24 cytokines/chemokines were assayed. IL-2 (+ 80%) and IL-13 (+ 83%) were greater with curcumin supplementation in the prevention arm. IL-2 (+ 192%), IL-13 (+ 87%), IL-17A (+ 81%) and fractalkine (+ 121%) were higher while RANTES was lower (- 22%) with curcumin supplementation in the treatment arm (p < 0.05 for all). RANTES concentrations also correlated significantly with hepatic pathology scores of inflammation (r = 0.417, p = 0.008). Select serum cytokines/chemokines were affected with curcumin supplementation in this female rat model of NASH. Moreover, curcumin's effect(s) on RANTES and its association with liver disease pathogenesis and progression may warrant further investigation.


Assuntos
Anti-Inflamatórios/farmacologia , Curcumina/farmacologia , Suplementos Nutricionais , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Animais , Tetracloreto de Carbono/administração & dosagem , Quimiocina CCL5/sangue , Quimiocina CCL5/genética , Quimiocina CX3CL1/sangue , Quimiocina CX3CL1/genética , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Esquema de Medicação , Feminino , Humanos , Interleucina-13/sangue , Interleucina-13/genética , Interleucina-17/sangue , Interleucina-17/genética , Interleucina-2/sangue , Interleucina-2/genética , Fígado/metabolismo , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Ratos , Ratos Wistar , Resultado do Tratamento
4.
J Med Food ; 22(9): 937-943, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31448992

RESUMO

Polysaccharide of Atractylodes macrocephala Koidz (PAMK) has been reported to have beneficial effects on regulation of immune responses in mammals and poultry. Nonetheless, the immunoregulatory mechanism of action of PAMK remains unclear. The Toll-like receptor 4 (TLR4) signaling cascade has been proved as a classic polysaccharide-regulated pathway. The aim of this study was to explore the effects of PAMK on the TLR4 signaling pathway in the regulation of spleen function in mice. Ninety-six 5-week-old BALB/c female mice were randomly allocated into four groups with three replicates per group and eight mice per replicate in a single-factor completely randomized experimental design. The control group was fed a basic diet (PAMK free); the other three groups were fed 100, 200, or 400 mg/kg PAMK for 28 days. The spleen index, concentrations of cytokines, and mRNA and protein expression levels of genes related to TLR4 signaling were determined in spleen tissue. Compared with the control group, the spleen index significantly increased in all treatment groups. Concentrations of interleukin 2 (IL-2), IL-4, interferon γ (IFN-γ), and tumor necrosis factor α (TNF-α) in the medium-PAMK group also increased significantly. PAMK in the medium-PAMK group significantly increased both mRNA and protein expression of TLR4, myeloid differentiation factor 88 (MyD88), TNFR-associated factor 6 (TRAF6), TRAF3, and nuclear factor kappa B (NF-κB) in the spleen. In conclusion, PAMK may increase immune-response capacity of the spleen in mice via TLR4-MyD88-NF-κB signaling.


Assuntos
Atractylodes/química , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Polissacarídeos/administração & dosagem , Baço/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Animais , Feminino , Interleucina-2/genética , Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/genética , Transdução de Sinais/efeitos dos fármacos , Baço/metabolismo , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
5.
Fish Shellfish Immunol ; 93: 1018-1027, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446082

RESUMO

In our previous study, a DNA plasmid encoding the VAA gene of Vibrio anguillarum was constructed and demonstrated to confer moderated protection against V. anguillarum challenge. Here, a bicistronic DNA vaccine (pVAA-IRES-IL2), co-expressing the VAA gene of V. anguillarum and Interleukin-2 (IL2) gene of flounder, was constructed to increase the protective efficacy of VAA DNA vaccine. The potential of pVAA-IRES-IL2 to express both VAA and IL2 in transfected HINAE cell lines was confirmed by immunofluorescence assay. Further, the variation of sIgM+, CD4-1+, CD4-2+ lymphocytes and production of VAA-specific antibodies in flounder, which was intramuscularly immunized with three DNA plasmids (pIRES, pVAA-IRES, pVAA-IRES-IL2), were investigated, respectively. The bacterial burden and relative percentage survival (RPS) of flounder exposed to V. anguillarum infection were both analyzed to evaluate the efficacy of bicistronic DNA plasmid. Our results revealed that the percentages of sIgM+, CD4-1+, CD4-2+ lymphocytes and antibodies specific to VAA were remarkably increased in pVAA-IRES or pVAA-IRES-IL2 immunized fish. Moreover, the co-expression of IL2 enhanced the immune response in response to VAA DNA vaccination, as shown by the higher percentages of sIgM+, CD4-1+, CD4-2+ lymphocytes and production of specific antibody. Importantly, the RPS in pVAA-IRES-IL2 and pVAA-IRES groups reached 64.1% and 51.3%, respectively, when compared with the 97.5% cumulative mortality in pIRES group. Furthermore, the number of V. anguillarum in liver, spleen and kidney of pVAA-IRES or pVAA-IRES-IL2 immunized flounder after V. anguillarum challenge was significantly reduced, as compared to that in pIRES group. These suggest that the bicistronic DNA vaccine can be an effective immunization strategy in inducing immune response against V. anguillarum infection and IL2 has the potential as the adjuvant for VAA DNA vaccine.


Assuntos
Proteínas de Bactérias/imunologia , Vacinas Bacterianas/imunologia , Doenças dos Peixes/imunologia , Linguados/imunologia , Interleucina-2/imunologia , Vibrio/imunologia , Animais , Proteínas de Bactérias/genética , Linhagem Celular , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Interleucina-2/genética , Vacinas de DNA/imunologia , Vibrioses/imunologia , Vibrioses/veterinária
6.
Vet Immunol Immunopathol ; 216: 109892, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446206

RESUMO

Cyclosporine and glucocorticoids are powerful immunosuppressive agents used to treat many inflammatory diseases in dogs. Cyclosporine inhibits calcineurin-dependent pathways of T cell activation and resultant T cell cytokine production, and glucocorticoids directly inhibit genes coding for cytokines. Little work has been done comparing the effects of these agents on T cell cytokine production in dogs. Our study measured T cell interleukin-2 (IL-2) and interferon-gamma (IFN-γ) production using flow cytometry and T cell IL-2 and IFN-γ gene expression using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in activated canine T cells incubated with cyclosporine and dexamethasone in vitro. For flow cytometric assays, diluted whole blood was cultured for 7 h in the presence of cyclosporine (10, 100, 500, and 1000 ng/mL) or dexamethasone (10 ng/mL, 100 ng/mL, 1 µg/mL, and 10 µg/mL). For qRT-PCR, whole blood was cultured for 5 h with the same drugs at the same concentrations, and RNA was then extracted from leukocytes. Flow cytometry and qRT-PCR both demonstrated inhibition of IL-2 and IFN-γ that was concentration-dependent in response to cyclosporine, and was more variable for dexamethasone. Quantitative RT-PCR but not flow cytometry documented significant reduction of IL-2 expression after dexamethasone treatment, while both methods showed concentration-dependent suppression of IFN-γ. Quantitative RT-PCR also revealed additional cytokine suppression at higher cyclosporine concentrations, an effect not found using flow cytometry, and may therefore be the preferred method for cytokine determination in dogs. Suppression of IL-2 and IFN-γ in activated T cells may have potential as an indicator of the efficacy of cyclosporine and glucocorticoids in suppressing canine T cell function in vivo, and may therefore be of value for characterizing the immunosuppression induced by these drugs in clinical patients.


Assuntos
Ciclosporina/farmacologia , Dexametasona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interferon gama/metabolismo , Interleucina-2/metabolismo , Linfócitos T/efeitos dos fármacos , Animais , Ciclosporina/administração & dosagem , Dexametasona/administração & dosagem , Cães , Relação Dose-Resposta a Droga , Glucocorticoides/farmacologia , Imunidade Celular/efeitos dos fármacos , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Interferon gama/genética , Interleucina-2/genética
7.
Nat Commun ; 10(1): 3874, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462678

RESUMO

While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Imunoconjugados/farmacologia , Interleucina-2/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral/transplante , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/imunologia , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Imunoconjugados/genética , Imunoconjugados/uso terapêutico , Interleucina-2/genética , Interleucina-2/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade beta de Receptor de Interleucina-2/imunologia , Subunidade beta de Receptor de Interleucina-2/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Mutação , Neoplasias/imunologia , Neoplasias/patologia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Resultado do Tratamento
8.
Infect Immun ; 87(10)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31331960

RESUMO

In this study, a novel recombinant attenuated Yersinia pseudotuberculosis PB1+ strain (χ10069) engineered with ΔyopK ΔyopJ Δasd triple mutations was used to deliver a Y. pestis fusion protein, YopE amino acid 1 to 138-LcrV (YopENt138-LcrV), to Swiss Webster mice as a protective antigen against infections by yersiniae. χ10069 bacteria harboring the pYA5199 plasmid constitutively synthesized the YopENt138-LcrV fusion protein and secreted it via the type 3 secretion system (T3SS) at 37°C under calcium-deprived conditions. The attenuated strain χ10069(pYA5199) was manifested by the establishment of controlled infection in different tissues without developing conspicuous signs of disease in histopathological analysis of microtome sections. A single-dose oral immunization of χ10069(pYA5199) induced strong serum antibody titers (log10 mean value, 4.2), secretory IgA in bronchoalveolar lavage (BAL) fluid from immunized mice, and Yersinia-specific CD4+ and CD8+ T cells producing high levels of tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), and interleukin 2 (IL-2), as well as IL-17, in both lungs and spleens of immunized mice, conferring comprehensive Th1- and Th2-mediated immune responses and protection against bubonic and pneumonic plague challenges, with 80% and 90% survival, respectively. Mice immunized with χ10069(pYA5199) also exhibited complete protection against lethal oral infections by Yersinia enterocolitica WA and Y. pseudotuberculosis PB1+. These findings indicated that χ10069(pYA5199) as an oral vaccine induces protective immunity to prevent bubonic and pneumonic plague, as well as yersiniosis, in mice and would be a promising oral vaccine candidate for protection against plague and yersiniosis for human and veterinary applications.


Assuntos
Anticorpos Antibacterianos/biossíntese , Imunoglobulina A/biossíntese , Vacina contra a Peste/administração & dosagem , Peste/prevenção & controle , Proteínas Recombinantes de Fusão/administração & dosagem , Yersinia pestis/efeitos dos fármacos , Infecções por Yersinia pseudotuberculosis/prevenção & controle , Yersinia pseudotuberculosis/efeitos dos fármacos , Administração Oral , Animais , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/genética , Proteínas da Membrana Bacteriana Externa/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/microbiologia , Proteção Cruzada , Feminino , Expressão Gênica , Humanos , Imunização , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/microbiologia , Masculino , Camundongos , Peste/imunologia , Peste/microbiologia , Peste/mortalidade , Vacina contra a Peste/biossíntese , Vacina contra a Peste/genética , Vacina contra a Peste/imunologia , Plasmídeos/química , Plasmídeos/metabolismo , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Análise de Sobrevida , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Vacinas Sintéticas , Yersinia pestis/imunologia , Yersinia pestis/patogenicidade , Yersinia pseudotuberculosis/imunologia , Yersinia pseudotuberculosis/patogenicidade , Infecções por Yersinia pseudotuberculosis/imunologia , Infecções por Yersinia pseudotuberculosis/microbiologia , Infecções por Yersinia pseudotuberculosis/mortalidade
9.
Infect Immun ; 87(10)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31308085

RESUMO

The development of effective malaria vaccines is hampered by incomplete understanding of the immunological correlates of protective immunity. Recently, the moderate clinical efficacy of the Plasmodium falciparum circumsporozoite protein (CSP)-based RTS,S/AS01E vaccine in phase 3 studies highlighted the urgency to design and test more efficacious next-generation malaria vaccines. In this study, we report that immunization with recombinant CSP from Plasmodium yoelii (rPyCSP), when delivered in Montanide ISA 51, induced sterilizing immunity against sporozoite challenge in C57BL/6 and BALB/c strains of mice. This immunity was antibody dependent, as evidenced by the complete loss of immunity in B-cell-knockout (KO) mice and by the ability of immune sera to neutralize sporozoite infectivity in mice. Th2-type isotype IgG1 antibody levels were associated with protective immunity. The fact that immunized gamma interferon (IFN-γ)-KO mice and wild-type (WT) mice have similar levels of protective immunity and the absence of IFN-γ-producing CD4+ and CD8+ T cells in protected mice, as shown by flow cytometry, indicate that the immunity is IFN-γ independent. Protection against sporozoite challenge correlated with higher frequencies of CD4+ T cells that express interleukin-2 (IL-2), IL-4, and tumor necrosis factor alpha (TNF-α). In the RTS,S study, clinical immunity was associated with higher IgG levels and frequencies of IL-2- and TNF-α-producing CD4+ T cells. The other hallmarks of immunity in our study included an increased number of follicular B cells but a loss in follicular T helper cells. These results provide an excellent model system to evaluate the efficacy of novel adjuvants and vaccine dosage and determine the correlates of immunity in the search for superior malaria vaccine candidates.


Assuntos
Anticorpos Antiprotozoários/biossíntese , Imunoglobulina G/biossíntese , Vacinas Antimaláricas/biossíntese , Malária/prevenção & controle , Plasmodium yoelii/imunologia , Proteínas de Protozoários/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/parasitologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/parasitologia , Feminino , Imunização , Imunogenicidade da Vacina , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Malária/genética , Malária/imunologia , Malária/parasitologia , Vacinas Antimaláricas/administração & dosagem , Manitol/administração & dosagem , Manitol/análogos & derivados , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ácidos Oleicos/administração & dosagem , Oligodesoxirribonucleotídeos/administração & dosagem , Proteínas de Protozoários/genética , Proteínas de Protozoários/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Vacinas de Subunidades
10.
Fish Shellfish Immunol ; 93: 55-65, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31319204

RESUMO

Interleukin-2 (IL-2) is mainly produced by CD4+ T helper lymphocytes, which is an important immunomodulatory cytokine that primarily promotes activation, proliferation and differentiation of T cells. In the present study, flounder (Paralichthys olivaceus) interleukin 2 homologue (poIL-2) was identified for the first time, and its expression patterns were characterized in healthy, virus- or bacteria-infected flounder. The full-length cDNA sequences of poIL-2 was 989 bp with an open reading frame of 423 bp coding a polypeptide of 140 amino acids (aa). The deduced aa sequences shared low similarities (<53%) with other known fish IL-2s. Multiple alignment of aa sequences revealed that poIL-2 own the classical IL-2 family signature of "C-X(3)-EL-X(2)-(T/V)-(V/M/L)-(K/T/R)-X-EC" and "DS-X-(F/L)Y(A/T/S)P". In healthy flounder, IL-2 mRNA was highly expressed in PBLs, spleen and hindgut, and moderately expressed in gill, trunk kidney and stomach. PHA, LPS and Con-A could effectively induce poIL-2 expression in primary cultured peripheral blood leukocytes in vitro. poIL-2 transcripts were significantly up-regulated in spleen, kidney, gill and hindgut post infections with Edwardsiella tarda and Hirame novirhabdovirus (HIRRV). The eukaryotic expression vector encoding poIL-2 (pcIL-2) was constructed and intramuscularly injected, which could be successfully expressed in flounders and induced significantly higher expressions of six immune related genes including poIL-2, ß-defensin, CD4-1, CD8α, IFN-γ and TNF-α compared with the injection with control plasmid. Moreover, pretreatment with pcIL-2 could markedly increase the survival rate of flounder challenged with HIRRV. Our results demonstrated that poIL-2 plays an important role in the induction of immune responses and immune defense against bacterial and virus infection, which indicated its potential use as an immunopotentiator to prevent diseases in flounder.


Assuntos
Doenças dos Peixes/imunologia , Linguados/genética , Linguados/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Interleucina-2/genética , Interleucina-2/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Edwardsiella tarda/fisiologia , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/veterinária , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica/veterinária , Interleucina-2/química , Novirhabdovirus/fisiologia , Filogenia , Infecções por Rhabdoviridae/imunologia , Infecções por Rhabdoviridae/veterinária , Alinhamento de Sequência/veterinária
11.
Food Funct ; 10(7): 3868-3879, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31184641

RESUMO

Lycopene (LYC) has been reported to exhibit antioxidant and immunoprotective activities, and our previous studies confirmed that LYC can alleviate multiple tissue damage induced by aflatoxin B1 (AFB1). However, it is unclear whether LYC could relieve the AFB1-induced immunosuppression. Thus, forty-eight male mice were randomly allocated and treated with LYC (5 mg kg-1) and/or AFB1 (0.75 mg kg-1) by intragastric administration for 30 days. We found that LYC alleviated AFB1-induced immunosuppression by relieving splenic structure injury and increasing the spleen weight, spleen coefficient, T lymphocyte subsets, the contents of IL-2, IFN-γ and TNF-α in serum, as well as the mRNA expression of IL-2, IFN-γ and TNF-α in spleen. Furthermore, LYC inhibited oxidative stress induced by AFB1via decreasing the levels of reactive oxygen species (ROS), hydrogen peroxide (H2O2) and malondialdehyde (MDA), while enhancing the total antioxidant capacity (T-AOC) and antioxidant enzyme activities. In addition, LYC also restrained splenic apoptosis through blocking mitochondria-mediated apoptosis in AFB1 intoxicated mice, presenting as the increase of mitochondrial membrane potential, and the decrease of cytoplasmic Cyt-c protein expression, cleaved Caspase-3 protein expression, Caspase-3/9 activities and mRNA expressions, as well as balancing the mitochondrial protein and mRNA expressions of Bax and Bcl-2. These results indicate that LYC can alleviate AFB1-induced immunosuppression by inhibiting oxidative stress and mitochondria-mediated apoptosis of mice spleen.


Assuntos
Aflatoxina B1/efeitos adversos , Apoptose/efeitos dos fármacos , Imunossupressão , Licopeno/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Caspase 3/genética , Caspase 3/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Peróxido de Hidrogênio , Interferon gama/sangue , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-2/sangue , Interleucina-2/genética , Interleucina-2/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Baço/lesões , Baço/patologia , Linfócitos T , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
12.
J Med Food ; 22(9): 896-906, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31216204

RESUMO

The present study investigated the immunomodulatory activity and associated mechanisms of heat-treated Lactobacillus plantarum LM1004 (HT-LM1004) in a cyclophosphamide (CTX)-induced mouse model of immunosuppression. HT-LM1004 induced phagocytic activity and nitric oxide production in RAW264.7 macrophages and stimulated the release of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, and IL-12p70. In mice with CTX-induced immunosuppression, oral HT-LM1004 administration restored thymus and spleen indices, including spleen weight. Consistent with the in vitro results, HT-LM1004 increased TNF-α, IFN-γ, IL-2, and IL-12p70 levels in mice after 14 days of treatment and enhanced the natural killer (NK) cell activity of splenocytes from mice with CTX-induced immunosuppression against YAC-1 lymphoma cells. The method of HT-LM1004 generation influenced this activity: L. plantarum LM1004 grown in a membrane bioreactor, which reduced the size of the cells to <1.0 µm through physical stress (micronization), promoted NK cell cytotoxicity to a greater extent than LM1004 subjected to heat treatment alone. These findings indicate that HT-LM1004 without or with micronization can reverse CTX-induced immunosuppression without adverse side effects by potentiating NK cell function.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Ciclofosfamida/efeitos adversos , Fatores Imunológicos/administração & dosagem , Imunomodulação/efeitos dos fármacos , Lactobacillus plantarum/química , Probióticos/administração & dosagem , Animais , Antineoplásicos Alquilantes/administração & dosagem , Ciclofosfamida/administração & dosagem , Feminino , Temperatura Alta , Imunossupressão , Interferon gama/genética , Interferon gama/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Fagocitose/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
13.
Food Funct ; 10(6): 3671-3683, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31168539

RESUMO

In the present study, the effects of Lycium barbarum polysaccharides (LBPS) on immunoregulation and gut microbiota dysbiosis in cyclophosphamide (CTX)-induced mice were investigated to elucidate whether the attenuation of immunosuppression is related to the modulation of the gut microbiota. The results showed that administration of LBPS could protect immune organs (enhancing immune organ indexes and alleviating immune organ damage), enhance the production of immune-related cytokines (IL-2, IL-6, IL-1ß, TNF-α and IFN-γ) and prevent the hepatotoxicity in CTX-induced mice. Additionally, LBPS treatment could promote the production of short-chain fatty acids and modulate the composition of the gut microbiota, increasing the relative abundances of Bacteroidaceae, Lactobacillaceae, Prevotellaceae and Verrucomicrobiaceae, which were positively associated with immune traits. The present results indicated that LBPS might regulate the immune response depending on the modulation of the gut microbiota, suggesting that LBPS could be developed as special ingredients for immunoregulation in association with the modulation of the gut microbiota.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Disbiose/tratamento farmacológico , Disbiose/microbiologia , Microbioma Gastrointestinal , Lycium/química , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Ciclofosfamida/efeitos adversos , Disbiose/induzido quimicamente , Disbiose/imunologia , Frutas/química , Humanos , Imunidade , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
14.
Mol Cell Biol ; 39(16)2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31160491

RESUMO

T cells are nodal players in the adaptive immune response against pathogens and malignant cells. Alternative splicing plays a crucial role in T cell activation, which is analyzed mainly at later time points upon stimulation. Here we have discovered a 2-h time window early after stimulation where optimal splicing efficiency or, more generally, gene expression efficiency is crucial for successful T cell activation. Reducing the splicing efficiency at 4 to 6 h poststimulation significantly impaired murine T cell activation, which was dependent on the expression dynamics of the Egr1-Nab2-interleukin-2 (IL-2) pathway. This time window overlaps the time of peak IL-2 de novo transcription, which, we suggest, represents a permissive time window in which decreased splicing (or transcription) efficiency reduces mature IL-2 production, thereby hampering murine T cell activation. Notably, the distinct expression kinetics of the Egr1-Nab2-IL-2 pathway between mouse and human render human T cells refractory to this vulnerability. We propose that the rational temporal modulation of splicing or transcription during peak de novo expression of key effectors can be used to fine-tune stimulation-dependent biological outcomes. Our data also show that critical consideration is required when extrapolating mouse data to the human system in basic and translational research.


Assuntos
Processamento Alternativo , Interleucina-2/genética , Linfócitos T/citologia , Animais , Proteína 1 de Resposta de Crescimento Precoce/genética , Regulação da Expressão Gênica , Humanos , Ativação Linfocitária , Camundongos , Proteínas Repressoras/genética , Transdução de Sinais , Especificidade da Espécie , Linfócitos T/imunologia , Fatores de Tempo , Pesquisa Médica Translacional
15.
J Immunol Res ; 2019: 9182979, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183395

RESUMO

The mechanism for pathogenesis of human papillomavirus (HPV) in the cervix has been investigated intensively. However, detailed differences in the distribution and function of innate immune cells between high-risk HPV types, especially during the chronic inflammation phase, have not been described fully. In this study, histologic pathology results of 245 women with HPV type 16 only (HPV16+) or type 18 only (HPV18+) were analyzed retrospectively from January 2015 to November 2016. More severe lesions of the cervix were observed in HPV16+ women compared with those in HPV18+ women. In total, 212 cervical brush specimens were collected from women suffering from chronic inflammation, HPV16+, or HPV18+ from December 2016 to December 2018. Flow cytometry analysis showed that abundant NK cells along with aberrant Treg cells were found in the HPV16-infected cervix. Quantitative real-time PCR demonstrated that higher expression levels of IFN-γ but muted IL-2 and KLRG-1 expression was detected in the cervix of patients with HPV16+ compared to HPV18+, which were further confirmed using 20 paraffin sections of cervical conization tissue. The ex vivo cytotoxicity experiment showed that the cytotoxicity of NK cells was significantly decreased in the cervix of HPV16+ patients compared with that of HPV18+ patients. Collectively, our results suggested that HPV16 disables the increased NK cells in the early lesion of the cervix, indicating that the local immune system of the cervix is hyporesponsive to HPV16 infection and this may explain its bias for malignant transformation.


Assuntos
Colo do Útero/patologia , Papillomavirus Humano 16/fisiologia , Papillomavirus Humano 18/fisiologia , Células Matadoras Naturais/imunologia , Infecções por Papillomavirus/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Células Cultivadas , Citotoxicidade Imunológica , Feminino , Regulação da Expressão Gênica , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Pessoa de Meia-Idade , Estudos Retrospectivos , Transativadores/genética , Transativadores/metabolismo
16.
Curr Med Sci ; 39(3): 363-370, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31209804

RESUMO

Respiratory syncytial virus (RSV) infection is the primary cause of respiratory disease in infants. The formalin-inactivated RSV (FI-RSV) vaccine resulted in an enhanced respiratory disease (ERD) in infants upon natural RSV infection, which is a major obstacle for development of safe and efficacious vaccines. Excessive and uncontrolled Th immune responses could be involved in the ERD. Agonists of TLRs are used as adjuvants to guide the type of immune response induced by vaccines. We evaluated the impact of lipopolysaccharide (LPS), the agonist of TLR4, on ERD as the adjuvant of FI-RSV. The results showed that LPS remarkably inhibited FI-RSV-enhanced lung inflammation, mucus production, airway inflammatory cell infiltration, and inflammatory cytokines following RSV challenge. Interestingly, LPS inhibited both Th2 and Th17 type cytokines in lungs of FI-RSV-immunized mice following RSV challenge, without an increase in the Th1 type cytokines, suggesting a controlled immune response. In contrast, Pam3Cys and Poly(I:C), the agonist of TLR1/2 or TLR3, partly inhibited FI-RSV-enhanced lung inflammation. Pam3Cys inhibited Th17 type cytokine IL-17, but promoted both Th1 and Th2 type cytokines. Poly(I:C) inhibited Th2 and Th17 type cytokines, but promoted Th1 type cytokines. In addition, LPS promoted IgG and IgG2a antibody production, which might provide protection from RSV challenge. These results suggest that LPS inhibits ERD without impairment in antibody production and protection, and the mechanism appears to be related with regulation of Th responses induced by FI-RSV.


Assuntos
Adjuvantes Imunológicos/farmacologia , Anticorpos Antivirais/biossíntese , Lipopolissacarídeos/farmacologia , Pneumonia/prevenção & controle , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Animais , Feminino , Formaldeído , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Lipoproteínas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/etiologia , Pneumonia/imunologia , Pneumonia/patologia , Poli I-C/farmacologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/virologia , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vírus Sinciciais Respiratórios/imunologia , Vírus Sinciciais Respiratórios/patogenicidade , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/virologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/virologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/virologia , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Receptor 3 Toll-Like/agonistas , Receptor 3 Toll-Like/genética , Receptor 3 Toll-Like/imunologia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Vacinação , Vacinas de Produtos Inativados
17.
PLoS One ; 14(5): e0216893, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120919

RESUMO

CD4+ effector/memory T cells (Tem) represent a leading edge of the adaptive immune system responsible for protecting the body from infection, cancer, and other damaging processes. However, a subset of Tem cells with low expression of CD45Rb (RbLoTem) has been shown to suppress inflammation despite their effector surface phenotype and the lack of FoxP3 expression, the canonical transcription factor found in most regulatory T cells. In this report, we show that RbLoTem cells can suppress inflammation by influencing Treg behavior. Co-culturing activated RbLoTem and Tregs induced high expression of IL-10 in vitro, and conditioned media from RbLoTem cells induced IL-10 expression in FoxP3+ Tregs in vitro and in vivo, indicating that RbLoTem cells communicate with Tregs in a cell-contact independent fashion. Transcriptomic and multi-analyte Luminex data identified both IL-2 and IL-4 as potential mediators of RbLoTem-Treg communication, and antibody-mediated neutralization of either IL-4 or CD124 (IL-4Rα) prevented IL-10 induction in Tregs. Moreover, isolated Tregs cultured with recombinant IL-2 and IL-4 strongly induced IL-10 production. Using house dust mite (HDM)-induced airway inflammation as a model, we confirmed that the in vivo suppressive activity of RbLoTem cells was lost in IL-4-ablated RbLoTem cells. These data support a model in which RbLoTem cells communicate with Tregs using a combination of IL-2 and IL-4 to induce robust expression of IL-10 and suppression of inflammation.


Assuntos
Asma/imunologia , Comunicação Celular/imunologia , Interleucina-10/imunologia , Interleucina-4/imunologia , Antígenos Comuns de Leucócito/imunologia , Modelos Imunológicos , Linfócitos T Reguladores/imunologia , Animais , Asma/genética , Asma/patologia , Comunicação Celular/genética , Modelos Animais de Doenças , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-10/genética , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-4/genética , Antígenos Comuns de Leucócito/genética , Camundongos , Camundongos Knockout , Pyroglyphidae/imunologia , Linfócitos T Reguladores/patologia
18.
J Exp Clin Cancer Res ; 38(1): 168, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30995926

RESUMO

BACKGROUND: Chimeric antigen receptor (CAR)-engineered T cells have displayed outstanding performance in the treatment of patients with hematological malignancies. However, their efficacy against solid tumors has been largely limited. METHODS: In this study, human osteosarcoma cell lines were prepared, flow cytometry using antibodies against CD166 was performed on different cell samples. CD166-specific T cells were obtained by viral gene transfer of corresponding DNA plasmids and selectively expanded using IL-2 and IL-15. The ability of CD166.BBζ CAR-T cells to kill CD166+ osteosarcoma cells was evaluated in vitro and in vivo. RESULTS: CD166 was selectively expressed on four different human osteosarcoma cell lines, indicating its role as the novel target for CAR-T cell therapy. CD166.BBζ CAR-T cells killed osteosarcoma cell lines in vitro; the cytotoxicity correlated with the level of CD166 expression on the tumor cells. Intravenous injection of CD166.BBζ CAR-T cells into mice resulted in the regression of the tumor with no obvious toxicity. CONCLUSIONS: Together, the data suggest that CD166.BBζ CAR-T cells may serve as a new therapeutic strategy in the future clinical practice for the treatment of osteosarcoma.


Assuntos
Antígenos CD/administração & dosagem , Moléculas de Adesão Celular Neuronais/administração & dosagem , Proteínas Fetais/administração & dosagem , Imunoterapia Adotiva/métodos , Osteossarcoma/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Ligante 4-1BB/administração & dosagem , Ligante 4-1BB/genética , Ligante 4-1BB/imunologia , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas Fetais/genética , Proteínas Fetais/imunologia , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-15/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Camundongos , Osteossarcoma/genética , Osteossarcoma/imunologia , Osteossarcoma/patologia , Receptores de Antígenos de Linfócitos T/administração & dosagem , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/administração & dosagem , Receptores de Antígenos Quiméricos/genética , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Microb Pathog ; 132: 30-37, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31004723

RESUMO

Previous studies on vaccine development against foot-and-mouth disease (FMD) virus reported that application of the inactivated vaccines for FMD virus is not completely effective. Novel vaccinations based on immune-dominant epitopes showed they induced immune responses. In addition, for better and safer immunization, access to of efficient adjuvants against FMD virus seems to be critical. In this study, we produced epitope recombinant vaccines from the VP1 protein of the FMD virus for serotype O of Iran that conjugated with Fc Immunoglobulin (FcIgG) and Interleukin-2 (IL-2). Multiple-epitope constructs included Polytope, Polytope-IL2-FcIgG, Polytope-IL2, Polytope-FcIgG that cloned and expressed in E. coli BL21 (DE3). To evaluate whether these epitope recombinant vaccines induce immune responses, BALB/c mice were injected with the epitope recombinant vaccines and their immune responses were compared with a negative control group. The humoral and cellular immune responses were measured by ELISA. The results showed there were significant differences between the negative control group and other immunized mice with recombinant epitope proteins (p < 0.05). The results of total IgG, IgG1, IgG2a levels and secretion of IFN-γ, IL-4 and IL-10 revealed that immune responses were enhanced when the epitope recombinant vaccine of FMD virus coupled with IL-2 and FcIgG. Observations indicated that the epitope recombinant plasmid of the VP1 protein co-expressed with IL-2 and FcIgG was effective in inducing an enhanced immune response. Therefore, IL-2 and FcIgG could be recommended as a potential adjuvant for epitope recombinant vaccine of the VP1 protein from FMD virus.


Assuntos
Vírus da Febre Aftosa/imunologia , Febre Aftosa/imunologia , Imunização , Epitopos Imunodominantes/imunologia , Fragmentos Fc das Imunoglobulinas/imunologia , Interleucina-2/imunologia , Vacinas Sintéticas/imunologia , Vacinas Virais/imunologia , Adjuvantes Imunológicos , Animais , Anticorpos Antivirais , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Modelos Animais de Doenças , Epitopos/genética , Epitopos/imunologia , Escherichia coli/genética , Feminino , Vírus da Febre Aftosa/genética , Imunidade Celular , Imunidade Humoral , Imunoglobulina G , Interferon gama , Interleucina-10 , Interleucina-2/genética , Interleucina-4 , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Vacinas Sintéticas/química , Vacinas Sintéticas/genética , Vacinas Virais/genética
20.
Tumour Biol ; 42(4): 1010428319843042, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30973070

RESUMO

Inflammation is an important etiological factor of colorectal carcinoma and may be related to colorectal carcinoma growth and proliferation. This study aimed to verify whether the presence of chronic inflammation represented by tumor necrosis factor-α, interleukin-2, interleukin-6, and interleukin-10 gene expression is related to hMLH1, hMSH2, hMSH6, and PMS2 gene expression and the corresponding protein levels of these genes from the DNA repair system. A total of 83 patients were operated on for curative or palliative colorectal carcinoma. Expression of the inflammatory response genes tumor necrosis factor-α, interleukin-2, interleukin-6, and interleukin-10 as well as expression of the hMLH1, hMSH2, hMSH6, and PMS2 genes of the DNA repair system (mismatch repair) and the expression levels of the corresponding mismatch repair proteins were measured in neoplastic tissue by reverse transcription polymerase chain reaction and immunohistochemistry, respectively. Associations were observed between hMSH6 mRNA expression and interleukin-2 mRNA expression (p = 0.026) as well as between hMLH1 and hMSH2 gene expression and tumor necrosis factor-α gene expression (p = 0.042). Higher tissue levels of interleukin-2 and tumor necrosis factor-α gene expression were associated with lower hMSH6, hMLH1, and hMSH2 gene expression.


Assuntos
Carcinogênese/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Inflamação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Inflamação/patologia , Interleucina-10/genética , Interleucina-2/genética , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Fator de Necrose Tumoral alfa/genética
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