Dendritic cells (DCs) comprise two functionally distinct subsets: plasmacytoid DCs (pDCs) and myeloid DCs (mDCs). pDCs are specialized in rapid and massive secretion of type I interferon (IFN-I) in response to nucleic acids through Toll like receptor (TLR)-7 or TLR-9. In this report, we characterized a CD56(+) DC population that express typical pDC markers including CD123 and BDCA2 but produce much less IFN-I comparing with pDCs. In addition, CD56(+) DCs cluster together with mDCs but not pDCs by genome-wide transcriptional profiling. Accordingly, CD56(+) DCs functionally resemble mDCs by producing IL-12 upon TLR4 stimulation and priming naïve T cells without prior activation. These data suggest that the CD56(+) DCs represent a novel mDC subset mixed with some pDC features. A CD4(+)CD56(+) hematological malignancy was classified as blastic plasmacytoid dendritic cell neoplasm (BPDCN) due to its expression of characteristic molecules of pDCs. However, we demonstrated that BPDCN is closer to CD56(+) DCs than pDCs by global gene-expression profiling. Thus, we propose that the CD4(+)CD56(+) neoplasm may be a tumor counterpart of CD56(+) mDCs but not pDCs.
Biomarkers ; metabolism ; CD56 Antigen ; genetics ; immunology ; Cell Lineage ; genetics ; immunology ; Dendritic Cells ; immunology ; metabolism ; pathology ; Gene Expression ; Hematologic Neoplasms ; genetics ; immunology ; pathology ; Humans ; Immunophenotyping ; Interferon Type I ; biosynthesis ; metabolism ; Interleukin-12 ; biosynthesis ; metabolism ; Interleukin-3 Receptor alpha Subunit ; genetics ; immunology ; Lectins, C-Type ; genetics ; immunology ; Membrane Glycoproteins ; genetics ; immunology ; Myeloid Cells ; immunology ; metabolism ; pathology ; Receptors, Immunologic ; genetics ; immunology ; Terminology as Topic ; Toll-Like Receptor 4 ; genetics ; immunology ; Toll-Like Receptor 7 ; genetics ; immunology ; Toll-Like Receptor 9 ; genetics ; immunology

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.
Amino Acids, Acidic ; Asthma ; Clone Cells ; DNA, Complementary ; Electrophoretic Mobility Shift Assay ; Gene Expression ; Inflammation ; Interleukin-2 ; Interleukin-4 Receptor alpha Subunit* ; Interleukin-4* ; Interleukins ; Janus Kinases ; Lymphoma ; Mutagenesis, Site-Directed ; Receptors, Interleukin-4 ; RNA ; Sensitivity and Specificity ; Serine

No abstract available.
Interleukin-4* ; Interleukins* ; Receptors, Interleukin-4* ; Rheumatic Diseases*

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.
Asthma* ; Cytokines ; Humans ; Interleukin-13 ; Interleukin-4 ; Interleukins ; Lung ; Receptors, Interleukin-13 ; Receptors, Interleukin-4

Dexamethasone is a widely used anti-inflammatory agent for a broad spectrum of diseases. The effectiveness of this agent is thought to be due to the capacity to modulate cytokine production in inflammatory cells. We examined the effects of dexamethasone on expressions of interferon gamma (IFN-gamma) and interleukin 4 (IL-4) by human peripheral blood mononuclear cells (PBMCs) in response to interleukin 12 (IL-12). Dexamethasone (10-5 M) inhibited IFN-gamma secretion, through direct suppression of IFN-gamma, IL-12 receptor (IL-12R) -beta1, and -beta2 expressions. Conversely dexamethasone increased IL-4 secretion as well as IL-4 expressions by PBMCs in response to IL-12. In addition, dexamethasone increased expression of suppressor of cytokine signalling (SOCS)-1, which inhibits JAK-STAT pathway of IL-12R signalling. The result of our study suggested that dexamethasone directly inhibited IFN-gamma expression, through suppression of IL-12 signalling and indirectly increases IL-4 expression, through suppression of IFN-gamma expression.
Dexamethasone* ; Humans ; Interferons ; Interleukin-12* ; Interleukin-4* ; Receptors, Interleukin-12

BACKGROUND: Collagen-induced arthritis (CIA) in mice is animal model of autoimmune disease known as rheumatic arthritis in human. We investigated CII-specific CD4+ T cell receptor usage in CIA mice. METHODS: In CIA model, draining lymph node (dLN) CD4+ T cells and splenocytes at 3rd, 5th, 8th week, we investigated CII-specific T cell proliferation, production of IL-17, IFN-gamma, TNF-alpha, IL-4 and IL-10. And we also performed anti-CII IgG Ab measurements in serum level, TCRVbeta usage and T cell clonality with RT-PCR-SSCP analysis. Also, we performed proliferative response against CII when CII-specific T cell subset is deleted. RESULTS: CIA mice showed more increase in the serum level of anti-CII IgG than normal mice after induction of arthritis. And the level of anti-CII IgG2a in CIA mice was increased after 3rd week after primary immunization, while anti-CII IgG1 was decreased. Draining LN CD4+T cells have proliferated against CII stimulation at 3rd week after 1st immunization. CD4+T cells derived from dLN of CIA mice produced proinflammatory cytokine IFN-gamma, IL-17 etc. Draining LN CD4 T cells of CIA presented higher proportion of CD4+Vbeta +subsets compared to those of normal mice at 3rd week after 1st immunization, and they were increased in proportion by CII stimulation. Draining LN CD4+ T cells without TCRVbeta +/Vbeta 8.1/8.2+/Vbeta 10b+cells were not responsive against CII stimulation. But, CII-reactive response of TCRVbeta 3-/Vbeta 8.1/8.2-/Vbeta 10b- T cells was recovered when Vbeta 3+ T cells were added in culture. CONCLUSION: Our results indicate that CD4+Vbeta 3+ T cells cells are selectively expanded in dLN of CIA mice, and their recovery upon CII re-stimulation in vitro, as well as the production Th1-type cytokines, may play pivotal role in CIA pathogenesis.
Animals ; Arthritis ; Arthritis, Experimental* ; Autoimmune Diseases ; Cell Proliferation ; Collagen Type II ; Cytokines ; Humans ; Immunization ; Immunoglobulin G ; Interleukin-10 ; Interleukin-17 ; Interleukin-4 ; Lymph Nodes ; Mice* ; Models, Animal ; Receptors, Antigen, T-Cell ; Rheumatic Fever ; T-Lymphocytes* ; Tumor Necrosis Factor-alpha

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.
Antioxidants ; Apoptosis ; Humans* ; Inflammation ; Interleukin-4* ; Leukocytes ; Monocytes* ; Oxygen ; Protein Kinase C ; Receptors, Interleukin-4

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.
Alleles ; Binding Sites ; Cell Count ; Eosinophils ; Genotype ; Humans ; Immunoassay ; Immunoglobulin E ; Interleukin-4* ; Receptors, Cytokine ; Receptors, Interleukin-4* ; Rhinitis*

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.
Carcinoma, Renal Cell* ; Cell Line* ; Cell Line, Tumor ; Gene Expression ; Humans* ; Interleukin-4* ; Receptors, Interleukin-4 ; RNA, Messenger

BACKGROUNDInterleukin-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.

METHODA 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.

RESULTSOnly 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).

CONCLUSIONSBoth 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.

Adult ; Asthma ; genetics ; Case-Control Studies ; Ethnic Groups ; Humans ; Interleukin-4 ; genetics ; Polymorphism, Single Nucleotide ; Receptors, Interleukin-4 ; genetics