RESUMO
BACKGROUND: Type 1 diabetes (T1D) is a serious chronic autoimmune condition. Even though the underlying reason for the onset of T1D is unknown, due to their effector and regulatory roles in immune responses, cytokines are essential in developing autoimmune disorders. Interleukin (IL)16 is an immunomodulatory cytokine implicated in several inflammatory and autoimmune diseases. OBJECTIVE: This study was designed to examine the association of IL16 gene polymorphisms, rs11556218 T > G and rs4778889 T > C, with the risk of T1D in Egyptian children. METHODS: Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, we analyzed rs11556218 T > G and rs4778889 T > C polymorphisms of the IL16 gene in 100 T1D subjects and 93 controls. RESULTS: Rs11556218 T > G polymorphism of the IL16 gene was not associated with the risk of developing T1D. Analysis of IL16 gene rs4778889 T > C showed that the TT genotype had a considerably higher risk of T1D than the TC genotype [OR = 2.195 (1.205-3.999)]. In comparison to patients with the C allele [OR = 0.6914 (0.38-1.2569)], patients with the T allele [OR = 1.45 (0.7956-2.6296)] were notably more likely to have T1D. A significant decrease was found in the frequency of GT (OR = 0.43, p = .03) and TC (OR = 0.32, p = .011) haplotypes of IL16 gene rs11556218 T > G and rs4778889 T > C polymorphisms in T1D patients compared with controls. CONCLUSION: IL16 gene rs4778889 T > C polymorphism might be associated with susceptibility to T1D. Egyptians with TT genotypes are more likely to develop T1D. However, GT and TC haplotypes of IL16 gene rs11556218 T > G and rs4778889 T > C polymorphisms highlight their protective role againstT1D disease.
Assuntos
Diabetes Mellitus Tipo 1 , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Interleucina-16 , Polimorfismo de Nucleotídeo Único , Humanos , Egito , Diabetes Mellitus Tipo 1/genética , Estudos de Casos e Controles , Criança , Masculino , Feminino , Interleucina-16/genética , Pré-Escolar , Alelos , Adolescente , HaplótiposRESUMO
BACKGROUND: Our previous study has reported that interleukin-16 (IL-16) genetic polymorphisms are significantly related to chronic hepatitis B (CHB) and hepatitis B virus-related (HBV-related) hepatocellular carcinoma (HCC). As CHB, liver cirrhosis (LC), and HCC are development processes, this study aimed to determine genetic correlation of IL-16 polymorphisms with HBV-related LC in a Chinese population. METHODS: IL-16 gene rs11556218, rs4072111, and rs4778889 polymorphism in 129 patients with HBV-related LC and 168 healthy individuals were genotyped via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). PCR-RFLP results were verified by DNA sequencing. RESULTS: The allelic and genotypic distributions of IL-16 rs11556218, rs4072111, and rs4778889 polymorphisms in HBV-related LC patients showed no significant difference from those in healthy controls. Furthermore, no relationship was observed between the haplotype distribution and susceptibility to HBV-related LC. CONCLUSIONS: This work provided the first evidence that the IL-16 genetic polymorphisms may not be associated with HBV-related LC risk.
Assuntos
Hepatite B Crônica , Interleucina-16 , Cirrose Hepática , Humanos , Estudos de Casos e Controles , China/epidemiologia , População do Leste Asiático , Predisposição Genética para Doença , Genótipo , Vírus da Hepatite B , Hepatite B Crônica/complicações , Hepatite B Crônica/genética , Interleucina-16/genética , Cirrose Hepática/genética , Cirrose Hepática/virologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Endometriosis is the presence of active ectopic endometrial glands and stroma at other sites outside the uterine cavity. It is a common cause of chronic pelvic pain which is sometimes debilitating, and inflammation is one of the known triggers of endometriosis. Interleukins 6 and 16 (IL-6 and IL-16) are proinflammatory cytokines which play essential roles in inflammatory diseases. We therefore investigated the relationship between genetic polymorphisms of interleukins 6 and 16, and the development of endometriosis in Nigerian women. METHOD: One hundred and thirty (130) consenting women were consecutively enrolled, sixty-five (65) of whom had endometriosis and 65 age-matched women as reference group, surgically confirmed as not having endometriosis. Spectrophotometric determination of serum concentrations of Interleukins 6 and 16 was carried out and the genotyping of IL-6 (rs1800795) and IL-16 (rs4778889, rs11556218, rs4072111) genes were performed using TaqMan assays. RESULTS: Serum IL-16 concentration was significantly higher in women with severe chronic pelvic pain compared to those with mild pain (p = 0.023). The C allele of rs4778889 was associated with endometriosis (OR: 1.80, 95% CI: 1.08 - 3.02, p = 0.024). CONCLUSION: Serum IL-16 and IL-16 rs4778889 may be important markers for endometriosis in Nigerian, and by extension, African women. Multicentre African studies would clarify this.
Assuntos
Dor Crônica , Endometriose , Humanos , Feminino , Endometriose/genética , Endometriose/complicações , Interleucina-16/genética , Predisposição Genética para Doença , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Dor Pélvica/genética , Dor Pélvica/complicações , Dor Crônica/complicações , Estudos de Casos e ControlesRESUMO
BACKGROUND: Cytokines play an important role in the immune response, angiogenesis, cell growth, and differentiation in hepatocellular carcinoma (HCC). OBJECTIVE: We performed a comprehensive study to identify tumor-related cytokines and pathways involved in HCC pathogenesis. METHODS: Cytokine production was evaluated in human HCC tissues and adjacent non-tumor tissues using an antibody-based protein array technique. We compared cytokine expression in HCC tissues with that of hepatic hemangioma (HH), liver metastasis of colorectal cancer, and noncancerous liver tissues from transplantation donors. The protein levels and localization of the candidate cytokines were analyzed by western blotting and immunohistochemistry. RESULTS: Increased expression of interleukin (IL)-1 receptor antagonist, macrophage migration inhibitory factor, and IL-16 was observed in HCC and paired adjacent non-tumor tissues compared with noncancerous livers. In addition, there were increased IL-16 levels in HCC tissues compared with HH. IL-16 treatment significantly increased cell proliferation in vitro. The expression of extracellular signal-regulated kinase (ERK)1/2 and cyclin D1 was markedly increased in cells from two HCC cell lines, Huh7 and HepG2, in a dose- and time-dependent manner. Phosphorylated to total ERK1/2 ratio was increased in Huh7 cells following IL-16 50âng/ml, but not HepG2 cells. ERK phosphorylation have occurred earlier than protein accumulation at 48âh. Pretreatment with the ERK inhibitor, FR18024, or an anti-IL-16 antibody reduced the increase in IL-16 production in HCC cells. CONCLUSIONS: These results suggest that cell proliferation induced by IL-16 is mediated through the ERK pathway, thus, we identified a new factor associated with HCC tumor growth.
Assuntos
Carcinoma Hepatocelular/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-16/genética , Neoplasias Hepáticas/genética , Fígado/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Hemangioma/tratamento farmacológico , Hemangioma/genética , Hemangioma/patologia , Células Hep G2 , Humanos , Interleucina-16/antagonistas & inibidores , Interleucina-16/biossíntese , Interleucina-16/farmacologia , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Fatores Inibidores da Migração de Macrófagos/genética , Metástase Neoplásica , ProteômicaRESUMO
BACKGROUND: Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma (CTCL) that transforms from mature, skin-homing T cells and progresses during the early stages in the skin. The role of the skin microenvironment in MF development is unclear, but recent findings in a variety of cancers have highlighted the role of stromal fibroblasts in promoting or inhibiting tumorigenesis. Stromal fibroblasts are an important part of the cutaneous tumor microenvironment (TME) in MF. Here we describe studies into the interaction of TME-fibroblasts and malignant T cells to gain insight into their role in CTCL. METHODS: Skin from normal (n = 3) and MF patients (n = 3) were analyzed for FAPα by immunohistochemistry. MyLa is a CTCL cell line that retains expression of biomarkers TWIST1 and TOX that are frequently detected in CTCL patients. MyLa cells were cultured in the presence or absence of normal or MF skin derived fibroblasts for 5 days, trypsinized to detached MyL a cells, and gene expression analyzed by RT-PCR for MF biomarkers (TWIST1 and TOX), Th1 markers (IFNG, TBX21), Th2 markers (GATA3, IL16), and proliferation marker (MKI67). Purified fibroblasts were assayed for VIM and ACTA2 gene expression. Cellular senescence assay was performed to assess senescence. RESULTS: MF skin fibroblast showed increased expression of FAP-α with increasing stage compared to normal. Normal fibroblasts co-cultured with MyLa cells suppressed expression of TWIST1 (p < 0.0006), and TOX (p < 0.03), GATA3 (p < 0.02) and IL16 (p < 0.03), and increased expression of IFNG (p < 0.03) and TBX21 (p < 0.03) in MyLa cells. In contrast, MyLa cells cultured with MF fibroblasts retained high expression of TWIST1, TOX and GATA3. MF fibroblasts co-culture with MyLa cells increased expression of IL16 (p < 0.01) and IL4 (p < 0.02), and suppressed IFNG and TBX21 in MyLa cells. Furthermore, expression of MKI67 in MyLa cells was suppressed by normal fibroblasts compared to MF fibroblasts. CONCLUSION: Skin fibroblasts represent important components of the TME in MF. In co-culture model, normal and MF fibroblasts have differential influence on T-cell phenotype in modulating expression of Th1 cytokine and CTCL biomarker genes to reveal distinct roles with implications in MF progression.
Assuntos
Fibroblastos Associados a Câncer/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Linfoma Cutâneo de Células T/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Cutâneas/metabolismo , Microambiente Tumoral , Proteína 1 Relacionada a Twist/metabolismo , Actinas/genética , Actinas/metabolismo , Idoso , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Senescência Celular , Técnicas de Cocultura , Endopeptidases/genética , Endopeptidases/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/genética , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-16/genética , Interleucina-16/metabolismo , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/patologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Micose Fungoide/genética , Micose Fungoide/metabolismo , Micose Fungoide/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/citologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Linfócitos T/metabolismo , Proteína 1 Relacionada a Twist/genética , Vimentina/genética , Vimentina/metabolismoRESUMO
Cartilage oligomeric matrix protein (COMP) is a large, multifunctional extracellular protein that, when mutated, is retained in the rough endoplasmic reticulum (ER). This retention elicits ER stress, inflammation, and oxidative stress, resulting in dysfunction and death of growth plate chondrocytes. While identifying the cellular pathologic mechanisms underlying the murine mutant (MT)-COMP model of pseudoachondroplasia, increased midline-1 (MID1) expression and mammalian target of rapamycin complex 1 (mTORC1) signaling was found. This novel role for MID1/mTORC1 signaling was investigated since treatments shown to repress the pathology also reduced Mid1/mTORC1. Although ER stress-inducing drugs or tumor necrosis factor α (TNFα) in rat chondrosarcoma cells increased Mid1, oxidative stress did not, establishing that ER stress- or TNFα-driven inflammation alone is sufficient to elevate MID1 expression. Since MID1 ubiquitinates protein phosphatase 2A (PP2A), a negative regulator of mTORC1, PP2A was evaluated in MT-COMP growth plate chondrocytes. PP2A was decreased, indicating de-repression of mTORC1 signaling. Rapamycin treatment in MT-COMP mice reduced mTORC1 signaling and intracellular retention of COMP, and increased proliferation, but did not change inflammatory markers IL-16 and eosinophil peroxidase. Lastly, mRNA from tuberous sclerosis-1/2-null mice brain tissue exhibiting ER stress had increased Mid1 expression, confirming the relationship between ER stress and MID1/mTORC1 signaling. These findings suggest a mechanistic link between ER stress and MID1/mTORC1 signaling that has implications extending to other conditions involving ER stress.
Assuntos
Acondroplasia , Proteína de Matriz Oligomérica de Cartilagem , Sistemas de Liberação de Medicamentos , Alvo Mecanístico do Complexo 1 de Rapamicina , Acondroplasia/tratamento farmacológico , Acondroplasia/genética , Acondroplasia/patologia , Animais , Biomarcadores/metabolismo , Proteína de Matriz Oligomérica de Cartilagem/genética , Proteína de Matriz Oligomérica de Cartilagem/metabolismo , Linhagem Celular Tumoral , Condrócitos/metabolismo , Condrócitos/patologia , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/genética , Retículo Endoplasmático Rugoso/genética , Retículo Endoplasmático Rugoso/metabolismo , Retículo Endoplasmático Rugoso/patologia , Peroxidase de Eosinófilo/genética , Peroxidase de Eosinófilo/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-16/genética , Interleucina-16/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Transgênicos , Mutação/genética , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Proteínas/genética , Proteínas/metabolismo , Ratos , Transdução de Sinais/genética , Sirolimo/farmacologia , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitina-Proteína LigasesRESUMO
Kawasaki disease (KD) is an acute, self-limited vasculitis, mainly affecting children younger than 5 years old, with accompanying fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) is the standard treatment for KD; however, ~15% of patients are resistant to IVIG treatment. To identify protein coding genetic variants influencing IVIG resistance, we re-analyzed our previous genome-wide association study (GWAS) data from 296 patients with KD, including 101 IVIG non-responders and 195 IVIG responders. Five nonsynonymous SNPs (nsSNPs) in five immune-related genes, including a previously reported SAMD9L nsSNP (rs10488532; p.Val266Ile), were associated with IVIG non-response (odds ratio [OR] = 1.89-3.46, P = 0.0109-0.0035). In a replication study of the four newly-identified nsSNPs, only one in the interleukin 16 (IL16) gene (rs11556218, p.Asn1147Lys) showed a trend of association with IVIG non-response (OR = 1.54, P = 0.0078). The same IL16 nsSNP was more significantly associated with IVIG non-response in combined analysis of all data (OR = 1.64, P = 1.25 × 10-4). Furthermore, risk allele combination of the IL16 CT and SAMD9L TT nsSNP genotypes exhibited a very strong effect size (OR = 9.19, P = 3.63 × 10-4). These results implicate IL16 as involved in the mechanism of IVIG resistance in KD.
Assuntos
Resistência a Medicamentos/genética , Imunoglobulinas Intravenosas/administração & dosagem , Interleucina-16/genética , Síndrome de Linfonodos Mucocutâneos , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Síndrome de Linfonodos Mucocutâneos/genéticaRESUMO
Asthma is a chronic inflammatory disease that involves a variety of cytokines and cells. Interleukin-16 (IL-16) is highly expressed during allergic airway inflammation and is involved in its development. However, its specific mechanism of action remains unclear. In the present study, we used an animal model of ovalbumin (OVA)-induced allergic asthma with mice harboring an IL-16 gene deletion to investigate the role of this cytokine in asthma, in addition to its underlying mechanism. Increased IL-16 expression was observed during OVA-induced asthma in C57BL/6J mice. However, when OVA was used to induce asthma in IL-16-/- mice, a diminished inflammatory reaction, decreased bronchoalveolar lavage fluid (BALF) eosinophil numbers, and the suppression of OVA-specific IgE levels in the serum and BALF were observed. The results also demonstrated decreased levels of T helper type 2 (Th2) and Th17 cytokines upon OVA-induced asthma in IL-16-/- mice. Hence, we confirmed that IL-16 enhances the lung allergic inflammatory response and suggest a mechanism possibly associated with the up-regulation of IgE and the promotion of Th2 and Th17 cytokine production. This work explored the mechanism underlying the regulation of IL-16 in asthma and provides a new target for the clinical treatment of asthma.
Assuntos
Asma/metabolismo , Hiper-Reatividade Brônquica/metabolismo , Interleucina-16/metabolismo , Pulmão/metabolismo , Ovalbumina , Células Th17/metabolismo , Células Th2/metabolismo , Animais , Asma/imunologia , Asma/fisiopatologia , Asma/prevenção & controle , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Hiper-Reatividade Brônquica/prevenção & controle , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Broncoconstrição , Modelos Animais de Doenças , Feminino , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interleucina-16/deficiência , Interleucina-16/genética , Pulmão/imunologia , Pulmão/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Células Th17/imunologia , Células Th2/imunologiaRESUMO
Alteration in endogenous Interferon (IFN) system may profoundly impact immune cell function in autoimmune diseases. Here, we provide evidence that dysregulation in IFN-regulated genes and pathways are involved in B cell- and monocyte-driven pathogenic contribution to Multiple Sclerosis (MS) development and maintenance. In particular, by using an Interferome-based cell type-specific approach, we characterized an increased susceptibility to an IFN-linked caspase-3 dependent apoptotic cell death in both B cells and monocytes of MS patients that may arise from their chronic activation and persistent stimulation by activated T cells. Ongoing caspase-3 activation functionally impacts on MS monocyte properties influencing the STAT-3/IL-16 axis, thus, driving increased expression and massive release of the bio-active IL-16 triggering and perpetuating CD4+ T cell migration. Importantly, our analysis also identified a previously unknown multi-component defect in type I IFN-mediated signaling and response to virus pathways specific of MS B cells, impacting on induction of anti-viral responses and Epstein-barr virus infection control in patients. Taking advantage of cell type-specific transcriptomics and in-depth functional validation, this study revealed pathogenic contribution of endogenous IFN signaling and IFN-regulated cell processes to MS pathogenesis with implications on fate and functions of B cells and monocytes that may hold therapeutic potential.
Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Interferon Tipo I/genética , Monócitos/imunologia , Monócitos/metabolismo , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Transcriptoma , Adulto , Apoptose , Biomarcadores , Estudos de Casos e Controles , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Interferon Tipo I/metabolismo , Interleucina-16/genética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Regiões Promotoras Genéticas , Transdução de SinaisRESUMO
BACKGROUND: Previous studies indicate that genetic factors play an important role in the pathogenesis of IgA nephropathy (IgAN). To evaluate the association between single nucleotide polymorphisms (SNPs) in the 3'-untranslated region (3'-UTR) of genes and IgAN risk, we performed a case-control study in a Chinese Han population. MATERIALS: Twelve SNPs were selected and genotyped in 384 IgAN patients and 357 healthy controls. Odds ratio (OR) and 95% confidence intervals (CI) were calculated by logistic regression adjusted for age and gender. Multifactor dimensionality reduction (MDR) was used to analyze the interaction of SNP-SNP with IgAN risk. RESULTS: Our study demonstrated that IL-16 rs859 (OR = 0.75, p = 0.040) and CYP19A1 rs4646 (OR = 2.58, p = 0.017) polymorphism were related to the risk of IgAN. In stratified analyses by gender, CYP19A1 rs4646 (OR = 2.96, p = 0.015) and BACH1 rs372883 (OR = 1.81, p = 0.038) polymorphisms conferred susceptibility to IgAN in males. Besides, rs372883 reduced IgAN risk in females (OR = 0.44, p = 0.042). We also found rs859 polymorphism was correlated with grade I-II (OR = 0.42, p = 0.028) in subgroup analysis of Lee's classification. Additionally, we found rs4646 polymorphism was correlated with serum creatinine (p = 0.035). CONCLUSION: Our results suggested that the IL-16 rs859, CYP19A1 rs4646, and BACH1 rs372883 polymorphisms have potential roles in the genetic susceptibility to IgAN in Chinese Han population.
Assuntos
Regiões 3' não Traduzidas/genética , Predisposição Genética para Doença/genética , Glomerulonefrite por IGA/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Aromatase/genética , Povo Asiático , Fatores de Transcrição de Zíper de Leucina Básica/genética , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Variação Genética , Humanos , Interleucina-16/genética , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores SexuaisRESUMO
Changes in the kidney structure in outbred and inbred male BALB/c mice were analyzed in the acute period after infection with influenza viruses A/H5N1 (10 MLD50; 10 days) and A/H1N1 (1 MLD50; 30 days). Antibodies to influenza viruses of both strains were most often expressed by endothelial cells of the glomeruli and arterioles and were rarely expressed by mesangiocytes and tubule epithelial cells. In the kidney, destructive processes induced by viruses and by ischemia due to massive blood vessel thrombosis. Mesangiocytes expressed factors, indicating that they could be qualified as M1 and M2 macrophages. Kidney destruction was more significant after infection of mice with the A/H5N1 virus, but in both experiments cell infiltrates were actually absent, probably due to blood vessel thrombosis and limited possibility of migration of mononuclear phagocytes and lymphocytes to the kidney.
Assuntos
Células Endoteliais/patologia , Vírus da Influenza A Subtipo H1N1/patogenicidade , Virus da Influenza A Subtipo H5N1/patogenicidade , Glomérulos Renais/patologia , Macrófagos/patologia , Células Mesangiais/patologia , Infecções por Orthomyxoviridae/patologia , Animais , Animais não Endogâmicos , Antígenos Virais/genética , Antígenos Virais/imunologia , Células Endoteliais/virologia , Expressão Gênica , Interações Hospedeiro-Patógeno , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/crescimento & desenvolvimento , Virus da Influenza A Subtipo H5N1/genética , Virus da Influenza A Subtipo H5N1/crescimento & desenvolvimento , Interleucina-16/genética , Interleucina-16/imunologia , Glomérulos Renais/irrigação sanguínea , Glomérulos Renais/virologia , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/imunologia , Macrófagos/virologia , Masculino , Células Mesangiais/virologia , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
CD9, a member of the tetraspanin superfamily, has been implicated in regulating various physiological processes, including cell motility, adhesion, apoptosis and metastasis. Recently, interleukin-16 (IL-16), a pro-inflammatory cytokine released by normal airway and alveolar epithelial cells, has been implicated as a possible ligand for CD9 as an alternative receptor. In this study, using A549 cells as a model of human alveolar epithelium, CD9 expression was ablated using CRISPR/Cas technology. Decreased expression of CD9 mRNA and protein levels was confirmed through RT-qPCR and flow cytometry, respectively. Individual clones were generated that expressed high levels of CD9 (wild-type, WT) or significantly less CD9 (knockdown, KD). Both wild-type and knockdown A549 cell migration was quantified using a FluoroBloc transwell chemotaxis assay. Our results indicate that wild-type A549 cells migrated towards chemoattractants. Moreover, CD9 expression was required in this process since the CD9 knockdown cells had a significantly reduced migration towards growth serum and IL-16. These results support the migratory properties for CD9 in human lung cells and support the hypothesis that CD9 serves as an alternative receptor for IL-16.
Assuntos
Movimento Celular/genética , Fatores Quimiotáticos/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Interleucina-16/genética , Neoplasias Pulmonares/genética , Tetraspanina 29/genética , Células A549 , Apoptose/genética , Linhagem Celular Tumoral , Humanos , Glicoproteínas de Membrana/genética , Transdução de Sinais/genéticaRESUMO
Circular ribonucleic acids are non-coding ribonucleic acids that can be identified from genome sequencing studies. Although they can be readily detected, their regulation and functional role in human diseases such as cancer are unknown. Using a systematic approach, we analyzed ribonucleic acid-sequencing data from a well-characterized cohort of intrahepatic cholangiocarcinoma to identify genetic pathways related to circular ribonucleic acids. Although the expression of most circular ribonucleic acids was similar in both the cancer and non-cancer tissues, expression of circ2174 was significantly increased in cancer tissues. Network analysis of co-related genes identified several pathways associated with circ2174, and common regulatory mediators between genes in these pathways and circ2174. Among these, alterations in several genes involved in interleukin-16 signaling responses such Lck, interleukin-16, and macrophage inflammatory protein-1-beta were the most prominent. Octamer transcription factor (Oct)-2 was identified as a signal transducer that was common to both circ2174 and interleukin-16. Circ2174 has sequence complementarity to miR149 which can target Oct-2. These data suggest a mechanism whereby circ2174 can act as a sponge to regulate the expression of miR149, and thereby modulate Oct-2 and interleukin-16 signaling pathways in cholangiocarcinoma.
Assuntos
Colangiocarcinoma/genética , MicroRNAs/genética , Fator 2 de Transcrição de Octâmero/genética , RNA/genética , Colangiocarcinoma/patologia , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes , Humanos , Interleucina-16/genética , RNA Circular , Transdução de SinaisRESUMO
Interleukin-12, 16 and 34 are important pro-inflammatory cytokines, some of the most important components of the innate immunity system. Herein, we identified interleukin-12A (lcIL12A), 16 (lcIL16) and 34 (lcIL34) in large yellow croaker (Larimichthys crocea), and determined their expression profile in unchallenged and challenged tissues. The coding sequence (CDS) of lcIL12A comprised 600 bp long encoding a protein of 199 amino acids (aa), the CDS of lcIL16 was 2454 bp encoding a protein of 817 aa, and the CDS of lcIL34 was 657 bp encoding a protein of 267 aa. Phylogenetic analysis revealed similar results to homology comparison that lcIL12A was closest to IL12A of Dicentrarchus labrax (73%) and Serola dumerili (73%), while lcIL16 had the closest relation to Lates calcarofer (72.6%), and lcIL34 to Sparus aurata (88.9%). Multiple sequence alignment showed these interleukins were highly conserved with other vertebrate interleukins in their functional domains. Further, quantitative real time PCR (qPCR) analysis revealed that lcIL12A, lcIL16 and lcIL34 were constitutively expressed in all examined tissues, with significantly higher expression in spleen, liver and kidney. This was especially true for lcIL34 gene. Importantly, when challenged with polyinosinic:polycytidylic acid (poly I:C) and Vibrio anguillarum (V. anguillarum), the mRNA expressions of these interleukins were up-regulated in liver, spleen and kidney. Their top values got over 4 folds at least relative to their expression at time 0, and even lcIL12 reached 13.37 fold at 12-h point in spleen. These suggested their anti-viral and anti-bacterial roles and their involvement in the innate immune response of Larimichthys crocea. These results would have major implications in improving our understanding of the functions of interleukins to defend against pathogen infections in teleost species.
Assuntos
Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Interleucinas/genética , Interleucinas/imunologia , Perciformes/genética , Perciformes/imunologia , Sequência de Aminoácidos , Animais , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Perfilação da Expressão Gênica , Subunidade p35 da Interleucina-12/química , Subunidade p35 da Interleucina-12/genética , Subunidade p35 da Interleucina-12/imunologia , Interleucina-16/química , Interleucina-16/genética , Interleucina-16/imunologia , Interleucinas/química , Filogenia , Poli I-C/farmacologia , Alinhamento de Sequência/veterinária , Vibrio/fisiologiaRESUMO
IL-16 is a pro-inflammatory cytokine originally designated as a lymphocyte chemoattractant factor. In mammal and avian, it has been characterized as an essential regulator of various cellular processes including cell recruitment and activation against pathogen invasion. So far, neither of the full-length of IL-16 homologue nor the response mechanism against pathogen was reported in crab species. In the present study, the pro-IL-16 homologue was firstly cloned and characterized from mud crab Scylla paramamosain. The full-length Sp-pro-IL-16 consisted of 4107 bp with an opening reading frame encoding 1369 amino acids. Multiple alignment analysis showed the putative amino acid sequence of Sp-pro-IL-16 had about 73.86% identity with Litopenaeus vannamei pro-IL-16. Additionally, two conserved PDZ domains and protein binding sites were found in Sp-pro-IL-16 and showed high similarities about 94.19% and 51.14% with their Litopenaeus vannamei and Mus musculus counterparts. RT-PCR analysis indicated that Sp-pro-IL-16 transcripts were constitutively expressed in all tissues examined with an extreme high level in hepatopancreas. Moreover, Sp-pro-IL-16 transcripts in hepatopancreas were significantly up-regulated 15-fold at 72 h after Vibrio alginolyticus challenge and 3.5-fold at 12 h after virus-analog Poly (I:C) challenge. The Western blot analysis revealed that Sp-pro-IL-16 can be cleaved to its bioactive form, an approximately 35 kDa mature IL-16, and the protein levels of both pro-IL-16 and mature IL-16 increased after Vibrio alginolyticus challenge. It is the first experimental identification of pro-inflammatory cytokine IL-16 in arthropods. This study could shed new light on further understanding of the response mechanism of pro-inflammatory cytokine IL-16 in Scylla paramamosain against pathogens. Meanwhile, it brought new insight into the origin and evolution of IL-16 in crab species.
Assuntos
Braquiúros/genética , Braquiúros/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Interleucina-16/genética , Interleucina-16/imunologia , Sequência de Aminoácidos , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Sequência de Bases , Perfilação da Expressão Gênica , Interleucina-16/química , Filogenia , Poli I-C/farmacologia , Distribuição Aleatória , Alinhamento de Sequência , Transcriptoma , Vibrio alginolyticus/fisiologiaRESUMO
OBJECTIVES: Gestational diabetes mellitus is a carbohydrate intolerance that occurs during pregnancy. Various inflammatory mediators are considered to be risk factors leading to GDM development. Among them are pro-inflammatory cytokines, such as IL16 and IL18. The aim of this study was to examine the association between IL16 and IL18 polymorphisms and GDM. MATERIAL AND METHODS: This study included 204 pregnant women with GDM and 207 pregnant women with normal glucose tolerance (NGT). All samples were genotyped in duplicate using allelic discrimination assays with TaqMan® probes. RESULTS: We observed that there was a decreased frequency of IL16 rs4778889 CC genotype carriers among women with GDM (CC vs. CT + TT: OR = 0.14; 95% CI = 0.02-1.15; p = 0.034). However, there was no significant difference in the distri-bution of alleles (C vs. T: OR = 0.81; 95% CI = 0.54-1.21; p = 0.30). There was a decreased frequency of the IL18 rs187238 G allele among GDM women (G vs. C: OR = 0.71; 95% CI = 0.53-0.96; p = 0.027). We also observed a decreased frequency of the IL18 rs1946518 T allele among women with GDM; however, this difference had only borderline statistical significance. We observed an association between IL18 rs187238, rs1946518 and BMI in pregnant women. CONCLUSIONS: The results of this study suggest that IL18 rs187238 and rs1946518 polymorphisms may be associated with an increased risk of GDM as well as with BMI in pregnant women.
Assuntos
Diabetes Gestacional/genética , Interleucina-16/genética , Interleucina-18/genética , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Frequência do Gene , Humanos , Polimorfismo Genético , Gravidez , Adulto JovemRESUMO
Gastric cancer (GC) is the second cause of cancer-related death worldwide. Interleukin (IL)-16 has a vital role in the development and homeostasis of the immune system. In the present study, we evaluated an exon variant rs4072111 C/T polymorphism and 3' UTR variant rs1131445 C/T within the miRNA binding with gastric cancer susceptibility in Iranian population. Genomic DNA was isolated from peripheral blood samples according to phenol chloroform extraction. The genotypes of IL-16 polymorphisms rs1131445 T/C and rs4072111 T/C were determined by polymerase chain reaction-restriction fragment length polymorphism method. In this case control study, a total of 256 patients with gastric cancer (238 cases (92.9 %) non-cardia and 18 cases (7.1 %) cardia) and 300 healthy control subjects were evaluated. In the present study, we found a significant association between rs4072111 of IL-16 gene and risk of GC in Iranian population. Individuals with CT genotype showed a significant association with 1.79-fold increased risk of GC (P = 0.008; adjusted OR 1.792; 95 % CI 1.164-2.759). The significant association was also detected for T allele of rs4072111 and increased risk of GC (P < 0.001; adjusted OR 1.981; 95 % CI 1.354-2.900). We also observed statistically a significant relationship between rs1131445 of IL-16 CT genotype and GC risk. Carriers of IL-16 CT genotype compared with TT genotype had 1.44 times higher increased likelihood of GC (P = 0.048; adjusted OR 1.445; 95 % CI 1.003-2.084). After stratification according to gender, we observed that in rs1131445, CT and CC male carriers had a higher risk of GC than females (P = 0.08; adjusted OR 1.608; 95 % CI 0.945-2.737 and P = 0.08; adjusted OR 2.186; 95 % CI 0.897-5.325, respectively). We also observed that for male carriers with C allele in rs1131445, there was a 1.53-fold higher risk of GC risk than female subjects (P = 0.029; adjusted OR 1.53; 95 % CI 1.04.4-2.248). We found that the rs1131445 T/C and rs4072111 T/C variants of IL-16 were significantly associated with increased risk of GC in Iranian population.
Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença/genética , Interleucina-16/genética , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/genética , Adulto , Idoso , Área Sob a Curva , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Razão de Chances , Reação em Cadeia da Polimerase , Curva ROC , Fatores de RiscoRESUMO
BACKGROUND: Preterm birth is considered a multifactorial condition; however, emerging evidence suggests that genetic variation among individuals may have an important role. Prior studies have suggested that single-nucleotide polymorphisms associated with genes related to the immune system, and particularly the maternal inflammatory response, may be associated with an increased risk of preterm delivery. OBJECTIVE: The objective of the study was to identify single-nucleotide polymorphisms associated with spontaneous preterm birth <37 weeks within a cohort of African-American women. STUDY DESIGN: This is a secondary analysis of a randomized trial that evaluated periodontal disease and preterm birth. Women were enrolled between 6 and 20 weeks' gestation at 3 prenatal care clinics between 2004 and 2007. Maternal DNA samples were collected and analyzed using a custom 1536 single-nucleotide polymorphismgenotyping array designed to assess genes involved in inflammation. Women were included in this study if they self-identified as African American. We excluded women with a multiple gestation or an indicated preterm delivery. We performed allele- and genotype-based analyses to evaluate the association between spontaneous preterm birth and tag single-nucleotide polymorphisms. We used a logistic regression to adjust for prior preterm birth in our genotype-based analysis. In a subgroup analysis, we compared women who delivered at <34 weeks' gestation to women who delivered at term. Within the microarray, we identified ancestry informative markers and compared global ancestry estimates among women who delivered preterm with those who delivered at term. RESULTS: Of the 833 African-American women in the study with genotype data, 77 women (9.2%) had a spontaneous preterm birth, whereas 756 women delivered at term. In an allele-based analysis, 4 single-nucleotide polymorphisms related to the genes for protein kinase C-α (PRKCA) were associated with increased risk of spontaneous preterm birth <37 weeks, whereas a single single-nucleotide polymorphism related to fms-related tyrosine kinase 1 (FLT1) was associated with spontaneous preterm birth <34 weeks. A genotype-based analysis revealed similar associations between single-nucleotide polymorphisms related to the PRKCA genes and spontaneous premature delivery. Additionally, single-nucleotide polymorphisms related to matrix metalloproteinase-2 (MMP2), tissue inhibitor of matrix metalloproteinase-2 (TIMP2), and interleukin 16 (IL16) genes were associated with spontaneous preterm birth <37 weeks in genotype-based analysis. Genetic variants related to MMP2, matrix metalloproteinase-1 (MMP1), and leukemia inhibitory factor receptor antisense RNA 1 (LIFR-AS1) genes were associated with higher rates of preterm birth <34 weeks. Ancestry estimates were similar between the women who had a spontaneous preterm birth and those who delivered at term. CONCLUSION: We identified tag single-nucleotide polymorphisms related to 7 genes that are critical to inflammation, extracellular remodeling, and cell signaling that were associated with spontaneous preterm birth in African-American women. Specifically, we found a strong association with the PRKCA gene. Genetic variation in these regions of the genome may be important in the pathogenesis of preterm birth. Our results should be considered in the design of future genomic studies in prematurity.
Assuntos
Negro ou Afro-Americano/genética , Polimorfismo de Nucleotídeo Único , Nascimento Prematuro/genética , Adulto , Alelos , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Interleucina-16/genética , Metaloproteinase 2 da Matriz/genética , Trabalho de Parto Prematuro/genética , Gravidez , Proteína Quinase C-alfa/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Adulto JovemRESUMO
Interleukin-16 (IL-16) is a multifunctional pro-inflammatory cytokine that was previously found in association with complex disorders, and it is now cleared that this cytokine plays a critical role in regulation of cellular functions such as homoeostasis. Due to the complexity of endometriosis and its resemblance to cancer, we designed present case-control study to determine the effects of genetic polymorphisms of the human IL-16 gene on Iranian women's susceptibility to endometriosis. A total of 126 patients with endometriosis (stages I-IV) and 144 healthy women as control group were recruited to the study. We genotyped four single nucleotide polymorphisms of IL-16 gene (rs11556218 T>G, rs4778889 T>C, rs4072111 C>T and rs1131445 C>T). Genotyping was performed using PCR and restriction fragment length polymorphism. Our results showed that genotype distribution in two exonic polymorphisms including rs11556218 and rs4072111 was significantly different between Endometriosis patients and healthy individuals (P < 0.05). We have also found an association between rs4072111 and rs1131445 with progression to the severe stages (III-IV) of endometriosis (P < 0.05). Finally, we may conclude that IL-16 gene polymorphisms are highly associated with increased risk of endometriosis and could be considered as a susceptibility factor for endometriosis.
Assuntos
Endometriose/genética , Predisposição Genética para Doença/genética , Interleucina-16/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Endometriose/patologia , Feminino , Frequência do Gene , Genótipo , Humanos , Irã (Geográfico) , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Índice de Gravidade de Doença , Adulto JovemRESUMO
IL-16 plays an important role in affect the secretion of tumor-related inflammatory cytokines. We aimed to assess the role of interleukin-16 (IL-16) rs4778889 T/C and rs11556218 T/G polymorphisms in the occurrence of renal cell cancer (RCC). This study is composed of 274 RCC patients and 274 control subjects. Genotyping of polymorphisms was performed using polymerase chain reaction combined with restriction fragment length polymorphism analysis. All statistical analysis was carried out by the SPSS statistical software package, version 16.0 (SPSS Inc., Chicago, IL, USA). Using conditional logistic regression analysis, the TC and CC genotypes of rs4778889 exhibited a higher risk of RCC, with adjusted ORs (and 95%CIs) of 1.79 (1.23-2.62) and 2.67 (1.29-5.69), respectively. Moreover, under dominant and recessive models, individuals carried the rs4778889 polymorphism was exhibited elevated RCC risk, with adjusted ORs (and 95%CI) of 1.93 (1.35-2.76) and 2.11 (1.05-4.45), respectively. No significant differences were observed in rs11556218 genotype frequencies between the study groups. In conclusion, the results of our study reveal an association between the IL-16 rs4778889 polymorphism and heightened risk of RCC.