Biomarcadores e imunobiológicos na asma / Biomarkers and immunobiological agents in asthma

A maioria dos asmáticos é bem controlada com o uso de corticosteroides inalados e beta-agonistas de ação prolongada; contudo, uma proporção de pacientes não responde a esta terapia, e mantém controle limitado da doença. Este grupo experimenta exacerbações frequentes, e requer admissão hospitalar. O desenvolvimento de novos agentes biológicos e biomarcadores da doença abre novas avenidas para o tratamento. Nós revisamos as últimas informações pertinentes aos biomarcadores e agentes biológicos, e demonstramos como os pacientes podem ser identificados e se beneficiar destes tratamentos. As fontes de dados incluíram artigos originais, revisões e publicações indexados nos bancos de dados PubMed, MEDLINE, LILACS, SciELO e publicações on-line, nos últimos 15 anos. As informações mais recentes da medicina personalizada com análise genética e biomarcadores da inflamação Th2 permitiram identificar fenótipos de asma que incluem um fenótipo T2 alto. Estudos recentes dirigidos para IgE, IL-5, IL-13, IL-17 e para os receptores de cadeias alfa de IL-4 mostraram alguma eficácia em alguns pacientes fenotipados. Para aqueles sem evidência de inflamação Th2, nenhuma terapia específica foi identificada. A disponibilidade de biomarcadores e agentes bioterapêuticos que são dirigidos para IgE, interleucinas IL-5, IL-4, IL-13 e IL-17, são uma excitante modalidade de medicina molecular. Contudo, estes agentes bioterapêuticos somente são efetivos quando dirigidos para pacientes com fenótipos de asma específicos.

Most asthmatic individuals are well managed with inhaled corticosteroids and prolonged-action beta-agonists; however, some patients are unresponsive to therapy and attain limited disease control. The latter group experiences frequent exacerbations requiring hospital admission. The development of new biological agents and disease biomarkers has provided novel avenues for treatment. We review the latest information regarding biomarkers and biological agents and demonstrate how potential patients may be identified for treatment. Data sources included original articles, reviews, and published works indexed in PubMed, MEDLINE, LILACS, SciELO, and other online databases over the past 15 years. The latest findings from personalized medicine with genetic analysis and clinical biomarkers of Th2 inflammation have allowed the identification of asthma phenotypes including a T2-high phenotype. Recent studies targeting IgE, IL-5, IL- 13, IL-17, and the IL4 receptor alpha chain have shown some efficacy in phenotyped patients. For those without evidence of Th2 inflammation, no specific therapies have been identified. The availability of biomarkers and biotherapeutic agents targeting IgE, IL-5, IL-4, IL-13, and IL-17 is an exciting advance in molecular medicine. However, those biotherapeutic agents are effective only when used in patients with specific asthma phenotypes.

Correlations of IL-4R gene polymorphism and serum IgE levels with asthma predictive index / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the correlations of IL-4R gene polymorphism and serum IgE levels with asthma predictive index (API) in children.</p><p><b>METHODS</b>One hundred and sixty-seven children with positive API, 187 children with negative API and 203 healthy children (control group) were enrolled. PCR and DNA sequencing were used to identify genotypes of the Arg551Gln locus in IL-4R gene. Serum IgE levels were measured using ELISA.</p><p><b>RESULTS</b>There was no significant difference in the genotype frequencies of the Arg551Gln locus in IL-4R gene among the positive API, negative API and control groups. Serum IgE levels in the positive API group were significantly higher than in the negative API and control groups (P<0.01). In the positive API group, the children aged less than 2 years had significantly lower serum IgE levels than those aged over 2 years (P<0.01).</p><p><b>CONCLUSIONS</b>There is no correlation between the Arg551Gln polymorphism in IL-4R gene and API results. API positivity is correlated with elevated serum IgE levels. An older age (>2 years) may be a risk factor for increased serum IgE levels in children with positive API.</p>

IL-4 receptor alpha single-nucleotide polymorphisms rs1805010 and rs1801275 are associated with increased risk of asthma in a Saudi Arabian population

The IL-4 receptor alpha subunit [IL-4Ralpha], when associated with the common gamma chain receptor, or the IL-13Ralpha1 subunit, transduces signals to STAT6 in response to IL-4 and IL-13 stimulations. This results in a number of cell-specific responses including Th2 differentiation, lymphocyte proliferation and IgE production. Given the prominent role of IL-4Ralpha in allergic disorders, several single-nucleotide polymorphisms [SNPs] have been found associated with asthma and other atopic disorders, including rs1805010 [I75V] and rs1801275 [Q576R] SNPs; however, lack of significant association have also been reported for some ethnic groups. The objective of this study was to determine whether IL-4Ralpha rs1805010 and rs1801275 polymorphisms are associated with asthma in patients from Saudi Arabia. One hundred and ninety severe asthmatic patients [11-70 years old] and 194 healthy subjects of equivalent age range were recruited for blood donation. DNA was purified and genotyping for rs1801275 and rs1805010 polymorphisms in the IL-4Ralpha gene was performed by PCR amplification, followed by cycle sequencing of the purified PCR fragments using BigDye chain terminator and capillary electrophoresis. Pearson's Chi-square tests showed that the minor alleles, G, for both rs1805010 and rs1801275 SNPs, were significantly more frequent in asthmatics than in the healthy group [Yates' P < 0.05]; conversely, the major alleles, A, were significantly more frequent in healthy than in asthmatics [P < 0.05]. Concerning association analysis, odds for A/G-G/G genotypes were significantly higher to be associated with asthma predisposition [rs1801275: OR = 2.12; 95% CI = 1.39-3.22; P < 0.001*; rs1805010: OR = 1.6; 95% CI = 1.01-2.53; P < 0.05*; dominant model]. Analysis of gender-genotype interactions, with genders nested within A/G-G/G, indicated higher odds for females than males of significant association with asthma [rs1801275: OR = 5.19, 95% CI = 2.09-12.94*; rs1805010: OR = 3.73, 95% CI = 2.06-6.74*]. Rs1805010 and rs1801275 were in linkage disequilibrium [D' = 0.27; P < 0.0004*], with G-G haplotype being more frequent in asthmatics than in healthy subjects [OR = 2.43, 95% CI = 1.59-3.71*].The risk alleles, G, of IL-4Ralpha rs1805010 and rs1801275 SNPs and corresponding A/G-G/G genotypes were significantly associated with asthma predisposition in asthmatics from Saudi Arabia.

Association study of bronchial asthma with polymorphisms of IL-4 and IL-4R receptor genes / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To assess the association of polymorphisms of IL-4 gene (rs2243250, rs2243283) and IL-4R gene (rs1805012, rs1801275, rs1805010) with susceptibility to asthma among ethnic Chinese in Qingdao.</p><p><b>METHODS</b>For 400 asthma patients and 200 healthy subjects, above polymorphisms were detected with SnaPshot method.</p><p><b>RESULTS</b>For rs1805012, the frequency of TC genotype in the asthma group was significantly lower than the control group (8.8% vs. 15.5%, χ (2)= 6.498, P= 0.039), and so were the frequencies of TC+ CC genotypes (9.0% vs. 15.5%, χ (2) = 5.522, P= 0.019) and the C allele (4.6% vs. 7.7%, χ (2) = 4.729, P= 0.039). No significant difference was detected between the two groups in the frequency of the remaining four polymorphisms or the haplotypes formed by rs2243250 and rs2243283 (All P> 0.05).</p><p><b>CONCLUSION</b>This study has indicated that rs1805012 polymorphism of IL-4R gene is associated with asthma in ethnic Han Chinese from Qingdao region. TC+ CC genotypes have a protective role against asthma compared with TT genotype. However, polymorphisms of IL-4 gene are not associated with susceptibility to asthma.</p>

IL-4 Receptor alpha Polymorphisms May Be a Susceptible Factor for Work-Related Respiratory Symptoms in Bakery Workers

PURPOSE: The IL-4 and IL-4 receptor alpha (IL-4Ralpha) genes are the key candidate genes for atopy and asthma susceptibility. Exposure to wheat flour can cause IgE sensitization and respiratory symptoms in bakery workers. Therefore, we hypothesized that IL-4 and IL-4Ralpha single nucleotide polymorphisms (SNPs) may be involved in the pathogenic mechanism of baker's asthma. METHODS: Clinical and genetic data from 373 bakery workers were analyzed. A survey questionnaire, spirometry, and skin prick tests with wheat flour were performed. Serum-specific IgE, IgG1, and IgG4 to wheat flour were determined using ELISA. Five candidate IL-4 (-729 T>G, 589 T>C, and 33 T>C) and IL-4Ralpha (Ile75Val A>G and Gln576Arg A>G) SNPs were genotyped and analyzed. RESULTS: Workers with the G allele of IL-4Ralpha Ile75Val A>G had a significantly higher prevalence of work-related lower respiratory symptoms than those with the AA genotype (P=0.004, 16.0% vs. 2.9%). In the skin prick test, workers with the AA genotype of IL-4Ralpha Gln576Arg A>G had a significantly higher positive rate to wheat flour (P=0.015, 8.2% vs. 1.1%) than those with AG/GG genotype. No significant associations were found in the three genetic polymorphisms of IL-4. For the predicted probabilities, workers with the AA genotype of Gln576Arg A>G had a higher prevalence of IgG1 and IgG4 in response to wheat flour, according to increased exposure intensity (P=0.001 for IgG1 and P=0.003 for IgG4). CONCLUSIONS: These findings suggest that the IL-4Ralpha Ile75Val and Gln576Arg polymorphisms may be associated with work-related respiratory symptom development.

IL-4 Receptor alpha Polymorphisms May Be a Susceptible Factor for Work-Related Respiratory Symptoms in Bakery Workers

PURPOSE: The IL-4 and IL-4 receptor alpha (IL-4Ralpha) genes are the key candidate genes for atopy and asthma susceptibility. Exposure to wheat flour can cause IgE sensitization and respiratory symptoms in bakery workers. Therefore, we hypothesized that IL-4 and IL-4Ralpha single nucleotide polymorphisms (SNPs) may be involved in the pathogenic mechanism of baker's asthma. METHODS: Clinical and genetic data from 373 bakery workers were analyzed. A survey questionnaire, spirometry, and skin prick tests with wheat flour were performed. Serum-specific IgE, IgG1, and IgG4 to wheat flour were determined using ELISA. Five candidate IL-4 (-729 T>G, 589 T>C, and 33 T>C) and IL-4Ralpha (Ile75Val A>G and Gln576Arg A>G) SNPs were genotyped and analyzed. RESULTS: Workers with the G allele of IL-4Ralpha Ile75Val A>G had a significantly higher prevalence of work-related lower respiratory symptoms than those with the AA genotype (P=0.004, 16.0% vs. 2.9%). In the skin prick test, workers with the AA genotype of IL-4Ralpha Gln576Arg A>G had a significantly higher positive rate to wheat flour (P=0.015, 8.2% vs. 1.1%) than those with AG/GG genotype. No significant associations were found in the three genetic polymorphisms of IL-4. For the predicted probabilities, workers with the AA genotype of Gln576Arg A>G had a higher prevalence of IgG1 and IgG4 in response to wheat flour, according to increased exposure intensity (P=0.001 for IgG1 and P=0.003 for IgG4). CONCLUSIONS: These findings suggest that the IL-4Ralpha Ile75Val and Gln576Arg polymorphisms may be associated with work-related respiratory symptom development.

Association between the polymorphisms of interleukin-4, the interleukin-4 receptor gene and asthma / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Interleukin-4 (IL4) is one of the most important cytokines involved in a variety of allergic disorders, particularly, asthma. A number of genetic epidemiological studies have identified an association between the gene polymorphisms of IL4 and interleukin-4 receptor (IL4R) and asthma in different populations. However, these studies have been inconsistent and inconclusive. The aim of this study was to investigate the association between the single nucleotide polymorphism (SNP) of IL-4, IL-4R and asthma risk in case-controlled studies using meta-analysis.</p><p><b>METHOD</b>A genetic model-free approach was used to perform the meta-analysis. Asthma (atopy status nondefined), nonatopic and atopic asthma subgroups were separately analyzed. Next, the ethnic subgroup was analyzed. Heterogeneity and publication bias were also explored.</p><p><b>RESULTS</b>Only two polymorphisms of IL4 (rs2243250 and rs2070874) and four polymorphisms of IL4R (rs1801275, rs1805011, rs1805010, and rs1805015) were included in the meta-analysis. Polymorphisms rs2243250 and rs2070874 of IL-4 and rs1801275 and rs1805011 of IL4R were associated with asthma. The overall odds ratio (OR) of rs2243250 in the CC versus TT+TC genotypes was 0.84 (95% CI: 0.75-0.94), and the Z-test for the overall effect was 3.0 (P = 0.003). We obtained significant results from this polymorphism in the Caucasian ethnicity and adult groups. However, the overall OR of rs1801275 for the GG+AG versus AA genotype was 1.16 (95% CI: 1.00-1.35), and the Z-test for the overall effect was 1.87 (P = 0.06). Moreover, significant results were only obtained from the sub-group analysis in Asians (P = 0.02). In the rs1805011 polymorphism of IL4R, the overall OR for the CC +AC versus AA genotypes was 0.39 (95% CI: 0.16-0.95), and the Z-test for the overall effect was 2.08 (P = 0.04).</p><p><b>CONCLUSIONS</b>Both the IL4 and IL4R polymorphisms were associated with asthma. The rs2243250 polymorphism of IL4 was more important in the white and adult groups. Individuals who carried the C allele for rs2070874 of the IL4 gene demonstrated increased asthma risk compared to TT homozygotes. An individual with an AA genotype in rs1805011 of the IL4R gene was less likely to suffer from asthma compared to the other two genotypes.</p>

Relationship of TGF-β and IL-4R gene polymorphisms with risk of classical Hodgkin lymphoma / 中华血液学杂志

<p><b>OBJECTIVE</b>This study was aimed to analyze the relationship between single nucleotide polymorphisms of transforming growth factor-β1 G-800A and C-509T, interleukin-4 receptor V75I and susceptibility of CHL in adults.</p><p><b>METHODS</b>Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied to analyze the expressed alleles of the selected SNP loca. The relationship between genomic polymorphisms of TGF-β1 and IL-4R and susceptibility of CHL were coupled with clinical data.</p><p><b>RESULTS</b>TGF-β1G-800A and TGF-β1C-509T had obvious linkage equilibrium (D' = 0.879, r(2) = 0.83, P = 0.020). GT haplotype distribution frequencies in mixed cellularity Hodgkin lymphoma cases and control group were of 53.1% and 34.2%, respectively, with statistically significant (OR = 2.35, P = 0.000); distribution frequencies of mutant gene T/T in disease and control groups were of 38.8% and 15.3%, respectively, also with statistically significant (OR = 3.654, P = 0.000); frequencies of nodular sclerosis CHL patients with IL-4R V75I mutant gene A/A in disease and control groups were of 19.2% and 41.75%, respectively, also with statistically significant (OR = 3.156, P = 0.000).</p><p><b>CONCLUSION</b>Single nucleotide polymorphisms of TGF-β1 G-800A, C-509T and IL-4R V75I has a significant correlation with Chinese susceptibility to classical Hodgkin lymphoma.</p>

mRNA expression of chemokine receptors on peripheral blood mononuclear cells and correlation with clinical features in systemic lupus erythematosus patients / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To investigate the expressions of chemokine receptors and interleukin (IL) receptors on the peripheral blood mononuclear cells (PBMCs) from systemic lupus erythematosus (SLE) patients and their correlations with clinical features as well as SLE disease activity index (SLEDAI).</p><p><b>METHODS</b>The mRNA expressions of chemokine receptors and IL receptors on PBMCs of 93 SLE patients and 30 healthy controls were detected by reverse transcription-polymerase chain reaction, including CCR2, CCR3, CCR4, CCR5, CCR6, CCR8, CXCR3, CXCRS, CX3CR1, XCR1, IL-4R, and IL-10R. The clinical features of SLE patients were recorded. The correlations of chemokine receptors and IL receptors mRNA expressions with clinical features as well as SLEDAI were assayed using linear regression analysis.</p><p><b>RESULTS</b>The level of CCR5 mRNA in SLE patients (including active and inactive SLE) was significantly higher than that in healthy controls (P < 0.05), and there was no significant difference between active and inactive patients in this respect (P > 0.05). CX3CR1 mRNA expression significantly increased from healthy control to inactive SLE to active SLE in sequence. The others (except for CCR8, CXCR3, and IL-10R) in active SLE patients were significantly higher than those in both inactive SLE patients and healthy controls (all P < 0.05). There were positive correlations between SLEDAI and CCR2 (r = 0.424, t = 4.313, P < 0.001), CCR3 (r = 0.518, t = 5.410, P < 0.001), CCR4 (r = 0.376, t = 3.851, P < 0.001), CCR6 (r = 0.457, t = 4.513, P < 0.001), CXCR5 (r = 0.455, t = 4.629, P < 0.001), CX3CR1 (r = 0.445, t = 4.523, P < 0.001), as well as XCR1 (r = 0.540, t = 5.445, P < 0.001). And CCR5 mRNA expression level was positively correlated with IL-4R mRNA (r = 0.313, t = 2.353, P < 0.05). The patients with myositis and cutaneous vasculitis simultaneously showed lower levels of CCR5 and CX3CR1, and CCR5 expression was negatively correlated with the scores of SLEDAI in SLE cases accompanied by photosensitivity (r = 0.426, t = -2.155, P < 0.05).</p><p><b>CONCLUSION</b>Increased expressions of CCR5 and CX3CR1 on PBMCs may be indicators in clinical survey for SLE.</p>

Packaging and concentrating of high titer of retrovirus containing IL-4RA / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To construct a recombination retroviral expression vector pLNC-IL-4RA with high efficiency transfection and carrying a screening label.</p><p><b>METHODS</b>IL-4RA was inserted into retroviral vector pLNC-Laz to get recombination retroviral expression vector pLNC-IL-4RA and then transfected into packaging cell line PA317 by liposome transfection. The transfected PA317 cells were obtained and amplified by G418 pressure screening. The cell culture supernatants containing viruses were harvested and the viral titer was determined by NIH3T3 cells infection.</p><p><b>RESULTS</b>The G418 resistant clones were titrated and checked for the presence of replication virus. The results showed that the highest titer of viral supernatant was 1 x 10(4) CFU/mL. Genome DNA isolated from the cell clone of the highest titer showed the function gene, IL-4RA cDNA, had integrated into the genome of host cells verified by PCR.</p><p><b>CONCLUSIONS</b>The recombination retroviral vector pLNC-IL-4RA encoding IL-4RA after packaging PA317 cells have higher viral titer. This provides a basis for gene treatment of asthma.</p>

Association of Q576R polymorphism in the interleukin-4 receptor gene with serum IgE levels in children with asthma / 中国当代儿科杂志

<p><b>OBJECTIVE</b>Interleukin-4 plays a key role in the development of asthma. Overseas studies have shown that Q576R polymorphism in the interleukin-4 receptor (IL-4R) gene is related to asthma as well as increased serum IgE levels. This study was designed to investigate the association of Q576R polymorphism in IL-4R gene with childhood asthma and serum IgE levels.</p><p><b>METHODS</b>The polymorphism of IL-4R Q576R was determined by PCR/RFLP and serum total IgE level was measured using ELISA in 94 children with asthma. Sixty-eight healthy children served as controls.</p><p><b>RESULTS</b>The distribution frequency of heterozygous genotype Q576R (41%) and mutant allele R576 (26%) was significantly higher in children with asthma than that of controls (16% each) (P < 0.01; P < 0.05). The total serum IgE level between patients with genotype Q576R and Q576Q was not significantly different (225.78 +/- 51.43 IU/mL vs 163.24 +/- 31.32 IU/mL, P> 0.05).</p><p><b>CONCLUSIONS</b>The mutant R576 allele of IL-4R may be one of the candidate genes for susceptibility to asthma. Allele R576 of IL-4R is related to asthma but is irrelevant to the total serum IgE level in children with asthma.</p>

A Study of Susceptibility between Allergic Rhinitis and IL-4 Receptor alpha Gene Polymorphism Study in Korean / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: The IL-4 receptor (IL-4R) gene has been suggested as a candidate gene for atopic diseases. The IL-4R consists of two subunits: the alpha chain (IL-4Ralpha), which is a high-affinity IL-4 binding site shared with the IL-13R, and the common gamma chain shared with several other cytokine receptors that amplifies signalling of the alpha chain. A Gln551Arg polymorphism of the IL-4Ralpha gene was shown to be a gain-of-function mutation and was associated with atopy. We tested whether a Gln551Arg polymorphism of IL-4Ralpha gene is associated with allergic rhinitis, blood eosinophil counts and total serum IgE levels in the Korean population. SUBJECTS AND METHOD: Blood samples for genetic analysis were obtained from 192 individuals with allergic rhinitis and from 191 healthy subjects without atopic diseases. Polymerase chain reaction-based assay for IL-4Ralpha Gln551Arg was used for genotyping. Serum total IgE levels were determined by using the immunoassay. Eosinophil values were determined by eosinophil numbers per total cell numbers per microL . RESULTS: There were no differences in the frequencies of the genotypes of IL-4Ralpha in the controls and patients (p>0.05). The frequencies of the IL-4Ralpha Arg551 allele were statistically different between controls and patients (p>0.05). Blood eosinophil count and total serum IgE levels were not statistically different in the genotypes of IL-4Ralpha Gln551Arg in allergic rhinitis (p>0.05). CONCLUSION: Our result suggests that the IL-4Ralpha Gln551Arg polymorphism might not give susceptibility to the development of allergic rhinitis in Koreans.

IL-4/IL-13 Cytokine and Receptor in Asthma / 소아알레르기및호흡기학회지

Asthma is a chronic allergic inflammatory disease of lung. The initiation and progression of asthma is dependent on the cytokines interleukin (IL) -4 and IL-13 acting through related receptor complexes. Disease pathogenesis is effected by intracellular signaling pathways that couple primarily to specific motifs within the intracellular domain of the IL-4 receptor alpha chain (IL-4R alpha), a subunit that is common to the IL-4 and IL-13 receptor complexes. Neutralizing anti-cytokine strategies have proven to be highly successful on dissecting relevant effector pathways in experimental allergic disease, and are now entering clinical trials in human allergic disorders. Although there have been only a few clinical studies on the effects of cytokine modulators in asthma, this line of research and development appears promising.

Polymorphisms of IL-4, IL-4R alpha, and AICDA genes in adult allergic asthma / 华中科技大学学报（医学）（英德文版）

The relationship between 3 polymorphisms sites [interleulin-4 (IL-4), IL-4 receptor (IL-4R) alpha chain and activation-induced cytidine deaminase (AICDA)] and adult allergic asthma in China was studied. By using case-control method, DNA and clinical data were obtained from allergic asthmatic patients and compared with those in the control subjects. The subjects were genotyped for the IL-4 C-589T promoter polymorphism, the IL-4R alpha chain Q576R and the AICDA C8408T by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The results showed that the IL-4 C-589T was not associated with adult allergic asthma in China. However, the IL-4R alpha chain 576R/R and AICDA 8408T/T frequency was significantly increased in allergic asthma group as compared with that in the control group [odd ratio (OR) = 3.797 and 9.127, respectively; P < 0.01)] and was correlated with the increased plasma total IgE. These data suggested that the IL-4R alpha chain 576R/R and AICDA 8408T/T genotypes confer genetic susceptibility to adult allergic asthma in China.

Polymorphisms of IL-4, IL-4R alpha, and AICDA genes in adult allergic asthma / 华中科技大学学报（医学）（英德文版）

The relationship between 3 polymorphisms sites [interleulin-4 (IL-4), IL-4 receptor (IL-4R) alpha chain and activation-induced cytidine deaminase (AICDA)] and adult allergic asthma in China was studied. By using case-control method, DNA and clinical data were obtained from allergic asthmatic patients and compared with those in the control subjects. The subjects were genotyped for the IL-4 C-589T promoter polymorphism, the IL-4R alpha chain Q576R and the AICDA C8408T by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The results showed that the IL-4 C-589T was not associated with adult allergic asthma in China. However, the IL-4R alpha chain 576R/R and AICDA 8408T/T frequency was significantly increased in allergic asthma group as compared with that in the control group [odd ratio (OR) = 3.797 and 9.127, respectively; P < 0.01)] and was correlated with the increased plasma total IgE. These data suggested that the IL-4R alpha chain 576R/R and AICDA 8408T/T genotypes confer genetic susceptibility to adult allergic asthma in China.

Essential roles for ID-1 motif of interleukin-4 receptor alpha chain in interleukin-4 signaling / 천식및알레르기

BACKGROUND: Interleukin (IL)-4 is a pleiotropic cytokine that plays an important role in the pathogenesis of the allergic inflammation and asthma. Upon IL-4 receptor (IL-4R) engagement, a variety of signaling mediators, such as JAK kinases and STAT-6 are activated, leading to induction of IL-4 target gene expression including CD23 and germline C epsilon transcription. The function of a membrane-proximal domain of IL-4Ra, termed ID-1, remains to be characterized to date. OBJECTIVE: To assess whether the ID-1 domain mediates the induction of IL-4 target gene expression in a STAT-6-dependent manner. METHODS: The intracellular region of IL-4Ralpha was translationally fused to the extracellular region of IL-2Rbeta to provide ligand specificity to IL-2. Acidic amino acids and serine residues in the ID-1 domain of the chimeric receptor were substituted by site-directed mutagenesis. These receptor cDNAs were stably transfected to M12.4.1 murine B lymphoma cells. Following IL-2 stimulation, wild type and mutant clones for the ID-1 motif were subjected to FACS. RNA blotting and elecroporetic mobility shift assays to address the levels of CD23, germline C epsilon and STAT-6 inductions, respectively. RESULTS: ID-1 mutant clones were defective in gene induction of CD23 and germline C epsilon in response to IL-2 stimulation, as compared with wildtype clones. Moreover, IL-2-mediated STAT-6 activation was abolished in ID-1 mutant clones. CONCLUSION: These results demonstrate that the ID-1 domain of IL-4Ra is essential to induce IL-4 target gene expression through a STAT-6-dependent pathway.

Citoquinas: la internet biológica ¿futura terapia en el asma bronquial? / Cytokines: the biological internet, the future therapy of bronchial asthma?

Las citoquinas son polipéptidos producidos por variadas células nucleadas que actúan como intercomunicadores celulares. Participan en funciones de defensa y reparación del adño del organismo y restablecimiento de la homeostasis. En los últimos años y gracias al desarrollo de la biología molecular, ha sido posible identificar y producir en el laboratorio numerosas citoquinas disponibles en el tratamiento de diversas enfermedades. En el asma bronquial existe un desbalance de algunas citoquinas con predominio de la producción de las interleuquinas (ILs) dependientes de los linfocitos tipo Th-2, como IL-4 e IL-5, las cuales inducen la producción de IgE y la eosinofilia, respectivamente. Actualmente están en marcha estudios clínicos tendientes a bloquear o impedir la acción de la IL-4 e IL-5 mediante anticuerpos monoclonales anti-IL o mediante la acción inhibidora sobre estas citoquinas que ejerce la IL-12. En esta revisión bibliográfica se analiza el estado actual de esta nueva futura terapia del asma

Purturbation of Th1 / Th2 Balance by Interleukin 4 Receptor alpha Variant Q576R in Rheumatic Disease / 대한면역학회지

No abstract available.

Two Distinxt Apoptotic Pathway in Human Monocytes Mediated by IL-4 and Fas / 대한면역학회지

Apoptosis has ernerged as a key mechanism for regulating the number of leukocytes at sites of inflammation. Besides withdrawal of inflammatory stimuli, apoptosis of human monocytes can be directly triggered through two cell surface molecules, Fas and the IL-4 receptor. In contrast to Fas-mediated death which utilizes reactive oxygen intermediates (ROI) as instruments of death, IL-4-induced apoptosis of monocytes was neither blocked by antioxidants, nor accompanied by elevation of cellular ROI. Moreover, PMA which upregulates protein kinase C (PKC) inhibited IL-4-, but not Fas-mediated death. These data define a ROl-dependent, PKC-resistant Fas pathway, and a ROl-independent, PKC-susceptible IL-4 pathway of apoptosis. Monocyte apoptosis triggered by depletion of inflammatory mediators resembles the IL-4 pathway. Within the context of an inflammatory site, monocyte accumulation and depletion may be susceptible to manipulation through these pathways.

Interleukin-4 Receptor Expression on Human Renal Cell Carcinoma Cell Lines by a Reverse Transcription-Polymerase Chain Reaction / 대한비뇨기과학회지

Recently interleukin-4 (IL-4) has been suggested to be a promising therapeutic agent for the malignant tumors of both murine and human origin. The effect of IL-4 is mediated by IL-4 receptor (IL-4R), which has been shown to be expressed in many normal and tumor cell lines. We herein tested two cell lines of human renal cell carcinoma (RCC), Caki-1 and CURC-II, for the expression of IL-1R gene. On the reverse transcription-polymerase chain reaction study, both cell lines expressed IL-4R mRNA. The present study suggests that it would be worthwhile to investigate the anti-tumor effect of IL-4 on Caki-l and CIJRC-II, which may help to develop new therapeutic strategies for RCC using IL-4.