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author:("Wu, jiangling")
1.  ADAM17 cleaves CD16b (FcγRIIIb) in human neutrophils 
Biochimica et biophysica acta  2012;1833(3):680-685.
CD16b (FcγRIIIb) is exclusively expressed by human neutrophils and binds IgG in immune complexes. Cell surface CD16b undergoes efficient ectodomain shedding upon neutrophil activation and apoptosis. Indeed, soluble CD16b is present at high levels in the plasma of healthy individuals, which appears to be maintained by the daily turnover of apoptotic neutrophils. At this time, the principal protease responsible for CD16b shedding is not known. We show that CD16b plasma levels were significantly decreased in patients administered a selective inhibitor targeting the metalloproteases ADAM10 and ADAM17. Additional analysis with inhibitors selective for ADAM10 or ADAM17 revealed that only inhibition of ADAM17 significantly blocked the cleavage of CD16b following neutrophil activation and apoptosis. CD16b shedding by ADAM17 was further demonstrated using a unique ADAM17 function-blocking mAb and a cell-based ADAM17 reconstitution assay. Unlike human CD16, however, mouse CD16 did not undergo efficient ectodomain shedding upon neutrophil stimulation or apoptosis, indicating that this mechanism cannot be modeled in normal mice. Taken together, our findings are the first to directly demonstrate that ADAM17 cleaves CD16 in human leukocytes.
doi:10.1016/j.bbamcr.2012.11.027
PMCID: PMC3556181  PMID: 23228566
Neutrophil; metalloprotease; ADAM17; apoptosis; Fc receptor
2.  Functional Fcgamma Receptor Polymorphisms Are Associated with Human Allergy 
PLoS ONE  2014;9(2):e89196.
Objective
IgG Fc receptors (FcγRs) play important roles in immune responses. It is not clear whether FcγR receptors play a role in human asthma and allergy. The aim of current study was to investigate whether functional single nucleotide polymorphisms (SNPs) of FcγR genes (FCGR) are associated with human asthma and allergy.
Methods
Functional SNPs of FCGR2A (FcγRIIA-131His>Arg, rs1801274), FCGR2B (FcγRIIB-187Ile>Thr, rs1050501), FCGR2C (FcγRIIC-13Gln>Stop, rs10917661), FCGR3A (FcγRIIIA-158Val>Phe, rs396991), and FCGR3B variants (FcγRIIIB NA1 and NA2) were genotyped in an asthma family cohort including 370 atopy positive, 239 atopy negative, and 169 asthma positive subjects. The genotype and phenotype data (asthma, bronchial hyper-responsiveness, and atopy) of subjects were analyzed using family-based association tests (FBAT) and logistic regression adjusted for age and sex.
Result
The FcγRIIA-131His>Arg SNP is significantly associated with atopy in a family-based association test (P = 0.00287) and in a logistic regression analysis (P = 0.0269, OR 0.732, 95% CI: 0.555–0.965). The FcγRIIA-131His (or rs1801274-A) allele capable of binding human IgG2 has a protective role against atopy. In addition, the rare FcγRIIB-187Thr (or rs1050501-C) allele defective for the receptor-mediated inhibitory signals is a risk factor for atopy (P = 0.0031, OR 1.758, 95% CI: 1.209–2.556) and IgE production (P<0.001). However, variants of activating FcγRIIIA (rs396991), and FcγRIIIB (NA1 and NA2), and FcγRIIC (rs10917661) are not associated with asthma, BHR, and atopy (P>0.05).
Conclusions
FcγRIIA and FcγRIIB functional polymorphisms may have a role in the pathogenesis of allergy.
doi:10.1371/journal.pone.0089196
PMCID: PMC3931680  PMID: 24586589
3.  Genetic variations in Toll-like receptors (TLRs 3/7/8) are associated with systemic lupus erythematosus in a Taiwanese population 
Scientific Reports  2014;4:3792.
Toll-like receptors (TLRs), as innate immunity sensors, play critical roles in immune responses. Six SNPs of TLR3, TLR7, and TLR8 were genotyped to determine their associations with systemic lupus erythematosus (SLE) and clinical manifestations of SLE. TLR7 SNP rs3853839 was independently associated with SLE susceptibility in females (G vs. C: p = 0.0051). TLR7 rs3853839-G (G vs. C: p = 0.0100) and TLR8 rs3764880-G (recessive model: p = 0.0173; additive model: p = 0.0161) were associated with pericardial effusion in females relative to healthy females. Anti-SSA positive cases were more likely to have the dominant TLR7 rs179010-T allele than normal controls (p = 0.0435). TLR3 rs3775296-T was associated with photosensitivity (p = 0.0020) and anemia (p = 0.0082). The “G-G” haplotype of TLR7 rs3853839 and TLR8 rs3764880 increased risk of SLE in females (age adjusted p = 0.0032). These findings suggest that TLR variations that modify gene expression affect risk for SLE susceptibility, clinical phenotype development, and production of autoantibodies.
doi:10.1038/srep03792
PMCID: PMC3896912  PMID: 24445780
4.  Immune opsonins modulate BLyS/BAFF release in a receptor-specific fashion* 
TNF ligand superfamily member 13B (B-lymphocyte stimulator (BLyS), B cell activating factor (BAFF)) promotes primary B cell proliferation and immunoglobulin production. While the soluble form of BLyS/BAFF is thought to be the primary biologically active form, little is known about the regulation of its cleavage and processing. We provide evidence that Fcγ receptor cross-linking triggers a rapid release of soluble, biologically active BLyS/BAFF from myeloid cells. Surprisingly, this function is primarily mediated by FcγRI, but not FcγRIIa as defined by specific mAb, and can be initiated by both IgG and C reactive protein (CRP) as ligands. The generation of a B cell proliferation and survival factor by both innate and adaptive immune opsonins through engagement of an Fcγ receptor, which can also enhance antigen uptake and presentation, provides a unique opportunity to facilitate antibody production. These results provide a mechanism by which Fcγ receptors can elevate circulating BLyS levels and promote autoantibody production in immune complex mediated autoimmune diseases.
PMCID: PMC3684394  PMID: 18606652
Fc Receptors; Monocytes/Macrophages; Human; Autoimmunity
5.  Role of Activating FcγR Gene Polymorphisms in Kawasaki Disease Susceptibility and Intravenous Immunoglobulin Response 
Background
A functional polymorphism in the inhibitory IgG-Fc receptor FcγRIIB influences intravenous immunoglobulin (IVIG) response in Kawasaki Disease (KD) a vasculitis preferentially affecting the coronary arteries in children. We tested the hypothesis that the polymorphisms in the activating receptors (Fcγ RIIA, Fcγ RIIIA and Fcγ RIIIB) also influence susceptibility, IVIG treatment response, and coronary artery disease (CAD) in KD patients.
Methods and Results
We genotyped polymorphisms in the activating FcγRIIA, FcγRIIIA and FcγRIIIB genes using pyrosequencing in 443 KD patients, including 266 trios and 150 single parent-child pairs, in northwest US and genetically determined race with 155 ancestry information markers. We used the FBAT program to test for transmission disequilibrium and further generated pseudo-sibling controls for comparisons to the cases. The FcγRIIA-131H variant showed an association with KD (p = 0.001) with ORadditive = 1.51 [1.16–1.96], p = 0.002) for the primary combined population, which persisted in both Caucasian (p = .04) and Asian (p = .01) subgroups and is consistent with the recent genome-wide association study. We also identified over-transmission of FcγRIIIB-NA1 among IVIG non-responders (p = 0.0002), and specifically to Caucasian IVIG non-responders (p = 0.007). Odds ratios for overall and Caucasian non-responders were respectively 3.67 [1.75–7.66], p = 0.0006 and 3.60 [1.34–9.70], p = 0.01. Excess NA1 transmission also occurred to KD with CAD (ORadditive = 2.13 [1.11–4.0], p = 0.02).
Conclusion
A common variation in FcγRIIA is associated with increased KD susceptibility. The FcγRIIIB-NA1, which confers higher affinity for IgG compared to NA2, is a determining factor for treatment response. These activating FcγRs play an important role in KD pathogenesis and mechanism of IVIG anti-inflammatory.
doi:10.1161/CIRCGENETICS.111.962464
PMCID: PMC3444514  PMID: 22565545
coronary disease; pediatrics; Kawasaki disease; IVIG treatment response; FcγR
6.  FAS mRNA editing in human Systemic Lupus Erythematosus 
Human mutation  2011;32(11):1268-1277.
FAS/FASL system plays a central role in maintaining peripheral immune tolerance. Human SLE is a prototypic systemic autoimmune disease characterized by expansion of autoreactive lymphocytes. It remains unclear whether a defective FAS/FASL system is involved in the pathogenesis of SLE. In this study, we have discovered a novel nucleotide insertion in FAS mRNA. We demonstrate that this novel FAS mutation occurs at mRNA levels, likely through a site-specific mRNA editing process. The mRNA editing mutation is unique for human FAS because the similar mRNA editing event is absent in other human TNFR family genes with death domains (DR5, DR6, and TNFR1) and in murine FAS. The adenine insertion mutation in the coding region message causes the alteration of human FAS mRNA reading frame. Functionally, cells expressing the edited FAS (edFAS) were refractory to FAS-mediated apoptosis. Surprisingly, cells from SLE patients produced significantly more edFAS products compared to cells from normal healthy controls. Additionally, we demonstrated that persistent engagement of T cell receptor increases human FAS mRNA editing in human T cells. Our data suggest that the site-specific FAS mRNA editing mutation may play a critical role in human immune responses and in the pathogenesis of human chronic inflammatory diseases.
doi:10.1002/humu.21565
PMCID: PMC3196739  PMID: 21793106
FAS; mRNA editing; apoptosis; Systemic Lupus Erythematosus
7.  Identification of Short Hairpin RNA Targeting Foot-And-Mouth Disease Virus with Transgenic Bovine Fetal Epithelium Cells 
PLoS ONE  2012;7(8):e42356.
Background
Although it is known that RNA interference (RNAi) targeting viral genes protects experimental animals, such as mice, from the challenge of Foot-and-mouth disease virus (FMDV), it has not been previously investigated whether shRNAs targeting FMDV in transgenic dairy cattle or primary transgenic bovine epithelium cells will confer resistance against FMDV challenge.
Principal Finding
Here we constructed three recombinant lentiviral vectors containing shRNA against VP2 (RNAi-VP2), VP3 (RNAi-VP3), or VP4 (RNAi-VP4) of FMDV, and found that all of them strongly suppressed the transient expression of a FLAG-tagged viral gene fusion protein in 293T cells. In BHK-21 cells, RNAi-VP4 was found to be more potent in inhibition of viral replication than the others with over 98% inhibition of viral replication. Therefore, recombinant lentiviral vector RNAi-VP4 was transfected into bovine fetal fibroblast cells to generate transgenic nuclear donor cells. With subsequent somatic cell cloning, we generated forty transgenic blastocysts, and then transferred them to 20 synchronized recipient cows. Three transgenic bovine fetuses were obtained after pregnant period of 4 months, and integration into chromosome in cloned fetuses was confirmed by Southern hybridization. The primary tongue epithelium cells of transgenic fetuses were isolated and inoculated with 100 TCID50 of FMDV, and it was observed that shRNA significantly suppressed viral RNA synthesis and inhibited over 91% of viral replication after inoculation of FMDV for 48 h.
Conclusion
RNAi-VP4 targeting viral VP4 gene appears to prevent primary epithelium cells of transgenic bovine fetus from FMDV infection, and it could be a candidate shRNA used for cultivation of transgenic cattle against FMDV.
doi:10.1371/journal.pone.0042356
PMCID: PMC3414509  PMID: 22905125
8.  ERAP1 genetic variations associated with HLA-B27 interaction and disease severity of syndesmophytes formation in Taiwanese ankylosing spondylitis 
Arthritis Research & Therapy  2012;14(3):R125.
Introduction
Ankylosing spondylitis (AS) is a familial, heritable disease specified by syndesmophyte formation leading to an ankylosed spine. Endoplasmic reticulum aminopeptidase 1 (ERAP1) genetic variations have been widely proved to be associated with AS in several ethnic populations. The aim of this study was to investigate whether ERAP1 single nucleotide polymorphisms (SNPs) are associated with AS susceptibility and disease severity in Taiwanese.
Methods
Four ERAP1 SNPs (rs27037, rs27980, rs27044 and rs30187) were genotyped in 797 Taiwanese AS patients and 1,150 healthy controls. Distributions of genotype and alleles were compared between AS patients and healthy controls, and among AS patients stratified by clinical parameters.
Results
The SNP rs27037T allele appeared to be a risk factor for AS susceptibility (P = 5.5 × 10-5, OR 1.30, 95% CI: 1.15 to 1.48; GT+TT vs. GG P = 9.3 × 10-5, OR 1.49, 95% CI: 1.22 to 1.82). In addition, the coding SNP (cSNP) rs27044G allele (P = 1.5 × 10-4, OR 1.28, 95% CI: 1.13 to 1.46; CG+GG vs. CC, P = 1.7 × 10-3, OR 1.44, 95% CI: 1.15 to 1.81) and the cSNP rs30187T allele (P = 1.7 × 10-3, OR 1.23, 95% CI: 1.08 to 1.40; CT+TT vs. CC P = 6.1 × 10-3, OR 1.38, 95% CI: 1.10 to 1.74) were predisposing factors for AS. Notably, the rs27044G allele carriers (CG+GG vs. CC, P = 0.015, OR 1.59, 95% CI: 1.33 to 2.30) and rs30187T allele carriers (CT+TT vs. CC, P = 0.011, OR 1.63, 95% CI: 1.12 to 2.38) were susceptible to syndesmophyte formation in AS patients. Furthermore, two cSNPs (rs27044 and rs30187) strongly associated with HLA-B27 positivity in AS patients. Finally, the ERAP1 SNP haplotype TCG (rs27037T/rs27980C/rs27044G) is a major risk factor for AS (adjusted P <0.00001, OR 1.38, 95% CI: 1.12 to 1.58) in Taiwanese.
Conclusions
This study provides the first evidence of ERAP1 SNPs involving syndesmophyte formation. The interactions between ERAP1 SNPs and HLA-B27 play critical roles in pMHC I pathway processing contributing to the pathogenesis of AS in multiple populations.
doi:10.1186/ar3855
PMCID: PMC3446506  PMID: 22632381
9.  Human FasL Gene Is a Target of β-Catenin/T-Cell Factor Pathway and Complex FasL Haplotypes Alter Promoter Functions 
PLoS ONE  2011;6(10):e26143.
FasL expression on human immune cells and cancer cells plays important roles in immune homeostasis and in cancer development. Our previous study suggests that polymorphisms in the FasL promoter can significantly affect the gene expression in human cells. In addition to the functional FasL SNP -844C>T (rs763110), three other SNPs (SNP -756A>G or rs2021837, SNP -478A>T or rs41309790, and SNP -205 C>G or rs74124371) exist in the proximal FasL promoter. In the current study, we established three major FasL hyplotypes in humans. Interestingly, a transcription motif search revealed that the FasL promoter possessed two consensus T-cell factor (TCF/LEF1) binding elements (TBEs), which is either polymorphic (SNP -205C>G) or close to the functional SNP -844C>T. Subsequently, we demonstrate that both FasL TBEs formed complexes with the TCF-4 and β-catenin transcription factors in vitro and in vivo. Co-transfection of LEF-1 and β-catenin transcription factors significantly increased FasL promoter activities, suggesting that FasL is a target gene of the β-catenin/T-cell factor pathway. More importantly, we found that the rare allele (-205G) of the polymorphic FasL TBE (SNP -205C>G) failed to bind the TCF-4 transcription factor and that SNP -205 C>G significantly affected the promoter activity. Furthermore, promoter reporter assays revealed that FasL SNP haplotypes influenced promoter activities in human colon cancer cells and in human T cells. Finally, β-catenin knockdown significantly decreased the FasL expression in human SW480 colon cancer cells. Collectively, our data suggest that β-catenin may be involved in FasL gene regulation and that FasL expression is influenced by FasL SNP haplotypes, which may have significant implications in immune response and tumorigenesis.
doi:10.1371/journal.pone.0026143
PMCID: PMC3191176  PMID: 22022540
10.  KH906, a recombinant human VEGF receptor fusion protein, is a new effective topical treatment for corneal neovascularization 
Molecular Vision  2011;17:797-803.
Purpose
The purpose of the current study was to investigate the effect of topical administration of KH906 on corneal neovascularization (NV).
Methods
To induce corneal neovascularization, chemical cauterization of the corneas of the right eyes of forty-eight New Zealand white rabbits was performed by touching the central cornea with an 8-mm-diameter NaOH-soaked Whatman filter paper for 60 s. On the next day after modeling, the rabbits were randomly and equally divided into six groups: PBS control group, 0.1% dexamethasone group, 10 mg/ml Avastin group, 5 mg/ml KH906 group, 10 mg/ml KH906 group, and 20 mg/ml KH906 group. The rabbits in the six groups received topical administration of 50 μl of the different solutions on the cornea four times per day for 14 days. Corneal neovascularization was analyzed by slit-lamp biomicroscopy 10 and 14 days after chemical cauterization. Corneal fluorescein staining was performed to evaluate the extent of corneal epithelial defect on the 7th, 10th, and 14th days. The VEGF level of the cornea was evaluated by ELISA assay.
Results
On the 10th and 14th days after chemical cauterization, the length of the longest new vessel and the areas of corneal neovascularization in all KH906-treated groups were significantly reduced compared to those of the PBS-treated group (p<0.05). The VEGF level of the cornea in all KH906-treated groups was significantly decreased compared to that of the PBS-treated group (p<0.05). Corneal fluorescein staining showed that KH906 had no effect on corneal epithelial healing.
Conclusions
Topical administration of KH906 significantly inhibited alkali burn-induced corneal neovascularization in rabbits. The new eye drops of KH906 may have a broad application for human corneal neovascularization in the near future.
PMCID: PMC3081801  PMID: 21528000
12.  A novel AMPK activator from Chinese herb medicine and ischemia phosphorylate the cardiac transcription factor FOXO3 
Oleanolic Acid (OA) is a nature product extracted from Chinese Herb Medicine which is traditionally used as treatment of diabetes and ischemic heart diseases. Mounting evidence showed that AMP-activated protein kinase (AMPK) has cardioprotective effect against ischemic injury and the forkhead transcription factor 3 (FOXO3) was recently identified as a downstream target of AMPK. We hypothesize that OA may protect against ischemic dysfunction of cardiomyocytes via activation of AMPK signaling pathway. Male C57BL/6 mice which were subjected to in vivo regional cardiac ischemia stimulated AMPK Thr172 phosphorylation, as well as phosphorylation of downstream FOXO3 (Ser413) and acetyl CoA carboxylase (ACC). The natural product, OA, significantly stimulated cardiac AMPK activation in cardiomyocyes in time- and dose-dependent manners. The mechanism of AMPK activation by OA may be due to the loss mitochondrial membrane potential (Δψm) as shown by JC-1 fluorescence assay. Intriguingly, OA as an AMPK activator also triggered FOXO3 (Ser413) phosphorylation in cardiomyocytes. Furthermore, OA treatment can protect cardiomyocytes from contractile dysfunction induced by hypoxia. Taken together, the results indicated that both ischemia and OA stimulated cardiac AMPK phosphorylation, as well downstream FOXO3 phosphorylation. The cardioprotective effect of OA maybe associated with activation of AMPK signaling pathways.
PMCID: PMC2863317  PMID: 20445824
AMP-activated protein kinase (AMPK); ischemia; Forkhead transcription factor 3 (FOXO3); Oleanolic Acid (OA)
13.  A novel AMPK activator from Chinese herb medicine and ischemia phosphorylate the cardiac transcription factor FOXO3 
Oleanolic Acid (OA) is a nature product extracted from Chinese Herb Medicine which is traditionally used as treatment of diabetes and ischemic heart diseases. Mounting evidence showed that AMP-activated protein kinase (AMPK) has cardioprotective effect against ischemic injury and the forkhead transcription factor 3 (FOXO3) was recently identified as a downstream target of AMPK. We hypothesize that OA may protect against ischemic dysfunction of cardiomyocytes via activation of AMPK signaling pathway. Male C57BL/6 mice which were subjected to in vivo regional cardiac ischemia stimulated AMPK Thr172 phosphorylation, as well as phosphorylation of downstream FOXO3 (Ser413) and acetyl CoA carboxylase (ACC). The natural product, OA, significantly stimulated cardiac AMPK activation in cardiomyocyes in time- and dose-dependent manners. The mechanism of AMPK activation by OA may be due to the loss mitochondrial membrane potential (ΔΨm) as shown by JC-1 fluorescence assay. Intriguingly, OA as an AMPK activator also triggered FOXO3 (Ser413) phosphorylation in cardiomyocytes. Furthermore, OA treatment can protect cardiomyocytes from contractile dysfunction induced by hypoxia. Taken together, the results indicated that both ischemia and OA stimulated cardiac AMPK phosphorylation, as well downstream FOXO3 phosphorylation. The cardioprotective effect of OA maybe associated with activation of AMPK signaling pathways.
PMCID: PMC2863317  PMID: 20445824
AMP-activated protein kinase (AMPK); ischemia; Forkhead transcription factor 3 (FOXO3); Oleanolic Acid (OA)
14.  SU6656, a Selective Src Family Kinase Inhibitor, Used To Probe Growth Factor Signaling 
Molecular and Cellular Biology  2000;20(23):9018-9027.
The use of small-molecule inhibitors to study molecular components of cellular signal transduction pathways provides a means of analysis complementary to currently used techniques, such as antisense, dominant-negative (interfering) mutants and constitutively activated mutants. We have identified and characterized a small-molecule inhibitor, SU6656, which exhibits selectivity for Src and other members of the Src family. A related inhibitor, SU6657, inhibits many kinases, including Src and the platelet-derived growth factor (PDGF) receptor. The use of SU6656 confirmed our previous findings that Src family kinases are required for both Myc induction and DNA synthesis in response to PDGF stimulation of NIH 3T3 fibroblasts. By comparing PDGF-stimulated tyrosine phosphorylation events in untreated and SU6656-treated cells, we found that some substrates (for example, c-Cbl, and protein kinase C δ) were Src family substrates whereas others (for example, phospholipase C-γ) were not. One protein, the adaptor Shc, was a substrate for both Src family kinases (on tyrosines 239 and 240) and a distinct tyrosine kinase (on tyrosine 317, which is perhaps phosphorylated by the PDGF receptor itself). Microinjection experiments demonstrated that a Shc molecule carrying mutations of tyrosines 239 and 240, in conjunction with an SH2 domain mutation, interfered with PDGF-stimulated DNA synthesis. Deletion of the phosphotyrosine-binding domain also inhibited synthesis. These inhibitions were overcome by heterologous expression of Myc, supporting the hypothesis that Shc functions in the Src pathway. SU6656 should prove a useful additional tool for further dissecting the role of Src kinases in this and other signal transduction pathways.
PMCID: PMC86555  PMID: 11074000

Results 1-14 (14)