-
Nathalie Acevedo,
Annika Sääf,
Cilla Söderhäll,
Erik Melén,
Jami Mandelin,
Christina Orsmark Pietras,
Sini Ezer,
Piia Karisola,
Johanna Vendelin,
Gustav Boije Af Gennäs, [......],
Erika von Mutius,
Gert Doekes,
Charlotte Braun-Fahrländer,
Josef Riedler,
Marianne van Hage,
Mauro D'Amato,
Annika Scheynius,
Göran Pershagen,
Juha Kere, Ville Pulkkinen
[show abstract]
[hide abstract]
ABSTRACT: Retinoid acid receptor-related Orphan Receptor Alpha (RORA) was recently identified as a susceptibility gene for asthma in a genome-wide association study. To investigate the impact of RORA on asthma susceptibility, we performed a genetic association study between RORA single nucleotide polymorphisms (SNPs) in the vicinity of the asthma-associated SNP (rs11071559) and asthma-related traits. Because the regulatory region of a previously implicated asthma susceptibility gene, Neuropeptide S receptor 1 (NPSR1), has predicted elements for RORA binding, we hypothesized that RORA may interact biologically and genetically with NPSR1. 37 RORA SNPs and eight NPSR1 SNPs were genotyped in the Swedish birth cohort BAMSE (2033 children) and the European cross-sectional PARSIFAL study (1120 children). Seven RORA SNPs confined into a 49 kb region were significantly associated with physician-diagnosed childhood asthma. The most significant association with rs7164773 (T/C) was driven by the CC genotype in asthma cases (OR = 2.0, 95%CI 1.36-2.93, p = 0.0003 in BAMSE; and 1.61, 1.18-2.19, p = 0.002 in the combined BAMSE-PARSIFAL datasets, respectively), and strikingly, the risk effect was dependent on the Gln344Arg mutation in NPSR1. In cell models, stimulation of NPSR1 activated a pathway including RORA and other circadian clock genes. Over-expression of RORA decreased NPSR1 promoter activity further suggesting a regulatory loop between these genes. In addition, Rora mRNA expression was lower in the lung tissue of Npsr1 deficient mice compared to wildtype littermates during the early hours of the light period. We conclude that RORA SNPs are associated with childhood asthma and show epistasis with NPSR1, and the interaction between RORA and NPSR1 may be of biological relevance. Combinations of common susceptibility alleles and less common functional polymorphisms may modify the joint risk effects on asthma susceptibility.
PLoS ONE 01/2013; 8(4):e60111. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Activation of taste receptors (TAS2Rs) by bitter taste agonists has been reported to cause bronchodilation. The aim of this study was to extend the information on the effects of bitter taste agonists on responses induced by different contractile mediators in a standard airway physiology preparation. Isometric responses were assessed in guinea-pig trachea (GPT). TAS2R agonists were administered either to segments pre-contracted with different agonists for contraction, or given before challenge with the different contractile stimuli, including antigen in tissues from ovalbumin-sensitized animals. TAS2R mRNA expression on GPT epithelium and smooth muscle was measured with real-time PCR. Denatonium, chloroquine, thiamine and noscapine induced concentration-dependent relaxations (R(max): 98.3±1.6, 100.0±0.0, 100.0±0.0 and 52.3±1.1 % of maximum, respectively, in the presence of indomethacin) in segments pre-contracted with carbachol. The receptors for denatonium (TAS2R4, TAS2R10) and chloroquine, (TAS2R3, TAS2R10) were expressed in GPT. Whereas denatonium selectively inhibited contractions induced by carbachol, chloroquine uniformly inhibited contractions evoked by prostaglandin E(2), the thromboxane receptor agonist U-46619, leukotriene D(4), histamine or antigen. The effects of denatonium, but not those of chloroquine were partly inhibited by blockers of the large Ca(2+) activated K(+) channels and decreased by an increase of the level of pre-contraction. In conclusion, TAS2R agonists mediated strong relaxations and substantial inhibition of contractions in guinea-pig trachea. Chloroquine and denatonium had distinct patterns of activity indicating different signalling mechanisms. The findings reinforce the hypothesis that TAS2Rs are potential targets for the development of a new class of more efficacious agonists for bronchodilation.
AJP Lung Cellular and Molecular Physiology 09/2012; · 3.66 Impact Factor
-
Christina Orsmark Pietras,
Johanna Vendelin,
Francesca Anedda,
Sara Bruce,
Mikael Adner,
Lilli Sundman, Ville Pulkkinen,
Harri Alenius,
Mauro D'Amato,
Cilla Söderhäll,
Juha Kere
[show abstract]
[hide abstract]
ABSTRACT: Neuropeptide S Receptor 1 (NPSR1, GPRA, GPR154) was first identified as an asthma candidate gene through positional cloning and has since been replicated as an asthma and allergy susceptibility gene in several independent association studies. In humans, NPSR1 encodes two G protein-coupled receptor variants, NPSR1-A and NPSR1-B, with unique intracellular C-termini. Both isoforms show distinct expression pattern in asthmatic airways. Although NPSR1-A has been extensively studied, functional differences and properties of NPSR1-B have not yet been clearly examined. Our objective was to investigate downstream signalling properties of NPSR1-B and functional differences between NPSR1-A and NPSR1-B.
HEK-293 cells transiently overexpressing NPSR1-A or NPSR1-B were stimulated with the ligand neuropeptide S (NPS) and downstream signalling effects were monitored by genome-scale affymetrix expression-arrays. The results were verified by NPS concentration-response and time series analysis using qRT-PCR, cAMP and Ca²⁺ assays, and cAMP/PKA, MAPK/JNK and MAPK/ERK pathway specific reporter assays.
NPSR1-B signalled through the same pathways and regulated the same genes as NPSR1-A, but NPSR1-B yielded lower induction on effector genes than NPSR1-A, with one notable exception, CD69, a marker of regulatory T cells.
We conclude that NPSR1-B is regulating essentially identical set of genes as NPSR1-A, with few, but possibly important exceptions, and that NPSR1-A induces stronger signalling effects than NPSR1-B. Our findings suggest an isoform-specific link to pathogenetic processes in asthma and allergy.
BMC Pulmonary Medicine 06/2011; 11:39. · 1.33 Impact Factor
-
Ville Pulkkinen,
Kaisa Salmenkivi,
Vuokko L Kinnula,
Eva Sutinen,
Maija Halme,
Ulla Hodgson,
Juho Lehto,
Anne Jääskeläinen,
Heli Piiparinen,
Juha Kere,
Irmeli Lautenschlager,
Maija Lappalainen,
Marjukka Myllärniemi
[show abstract]
[hide abstract]
ABSTRACT: Herpesviruses could contribute to the lung epithelial injury that initiates profibrotic responses in idiopathic pulmonary fibrosis (IPF).
We identified herpesviral DNA from IPF and control lung tissue using a multiplex PCR-and microarray-based method. Active herpesviral infection was detected by standard methods, and inflammatory cell subtypes were identified with specific antibodies. Patients that underwent lung transplantation were monitored for signs of herpesviral infection.
A total of 11/12 IPF samples were positive for Epstein-Barr virus (EBV) and 10/12 for human herpesvirus 6B (HHV-6B) DNA. Control lung samples (n = 10) were negative for EBV DNA, whereas three samples were positive for HHV-6B. EBV-encoded RNA (EBER) was identified in nine IPF samples and localized mainly to lymphocytic aggregates. HHV-6B antigens were detected in mononuclear cells in IPF lung tissue. CD20+ B lymphocytic aggregates that were surrounded by CD3+ T cells were abundant in IPF lungs. CD23+ cells (activated B cells, EBV-transformed lymphoblasts, and dendritic cells) were observed in the aggregates. IPF patients had no signs of increased herpesviral activation after lung transplantation.
Inflammatory cells are the main source of herpesviral DNA in the human IPF lung. Diagnostic tools should be actively used to elucidate whether herpesviral infection affects the pathogenesis, progression, and/or exacerbation of IPF.
Annals of medicine 01/2011; 44(2):178-86. · 3.52 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Viral infections and abnormal host response are thought to cause epithelial injury in idiopathic pulmonary fibrosis (IPF). To understand IPF pathogenesis, we have used overexpression cell models and expression microarrays to discover genes networked with ELMO domain containing 2 (ELMOD2) gene genetically implicated in IPF. The identified pathways were confirmed in vitro, and ELMOD2 protein expression was characterized in tissue samples. Here 303 genes were significantly altered after ELMOD2 transfection of human alveolar epithelial A549 cell line. The enriched pathways were interferon induction, viral response, antigen processing and presentation, and I-/nuclear factor-kappaB signaling. ELMOD2 showed immunoreactivity in macrophages and type II alveolar epithelial cells in normal human lung. In A549 cells, forced expression of ELMOD2 increased type I and type III interferon mRNA expression, and ELMOD2-specific siRNA molecules inhibited expression of these antiviral cytokines in response to Toll-like receptor three (TLR3) activation. In human macrophages silencing of ELMOD2 inhibited TLR3-dependent expression of type I and type III interferon genes. Influenza A virus infection decreased ELMOD2 mRNA expression in A549 cells and macrophages suggesting negative regulation in viral infections. In summary, our results show that TLR3 pathway is dependent on ELMOD2.-Pulkkinen, V., Bruce, S., Rintahaka, J., Hodgson, U., Laitinen, T., Alenius, H., Kinnula, V. L., Myllärniemi, M., Matikainen, S., Kere, J. ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses.
The FASEB Journal 12/2009; 24(4):1167-77. · 5.71 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Idiopathic pulmonary fibrosis (IPF) (histopathology of usual interstitial pneumonia [UIP]) is a progressive disease with poor prognosis. Characteristic features of IPF/UIP include fibroblastic foci, which are patchy lesions of focal, disarranged myofibroblasts. GATA-6 is a transcription factor linked with cell differentiation. Its role in the development of IPF has not previously been investigated. We hypothesized that GATA-6 participates in the differentiation of fibroblasts into myofibroblasts in IPF/UIP lungs. The expression patterns of GATA-6, the mesenchymal marker alpha-smooth muscle actin (alpha-SMA), and markers for proliferation (Ki67) and apoptosis (caspase-3) were analyzed in human IPF/UIP tissue samples. The effects of GATA-6 overexpression and silencing were studied in cell cultures. The results show that the alpha-SMA-positive fibroblastic foci in IPF/UIP lungs are positive for GATA-6, but negative for Ki67 and caspase-3. Cultured human IPF/UIP fibroblasts expressed GATA-6 mRNA, whereas cells from the normal adult lung did not. In cultured A549 lung epithelial cells, the induction of GATA-6 by transforming growth factor-beta1 resulted in simultaneous expression of alpha-SMA and decrease of E-cadherin. The inhibition of GATA-6 expression in fibroblasts showed that GATA-6 mediates the alpha-SMA-inducing signal of transforming growth factor-beta1. In conclusion, the hallmark of IPF/UIP histopathology, the fibroblast focus, consists of differentiated, quiescent cells that prominently express GATA-6.
American Journal of Respiratory Cell and Molecular Biology 08/2009; 42(5):626-32. · 5.13 Impact Factor
-
S Bruce,
F Nyberg,
E Melén,
A James, V Pulkkinen,
C Orsmark-Pietras,
A Bergström,
B Dahlén,
M Wickman,
E von Mutius,
G Doekes,
R Lauener,
J Riedler,
W Eder,
M van Hage,
G Pershagen,
A Scheynius,
J Kere
[show abstract]
[hide abstract]
ABSTRACT: Little is known about the asthma candidate gene neuropeptide S receptor 1 (NPSR1) in relation to environmental exposures, but recent evidences suggest its role as an effect modifier.
To explore the interaction between NPSR1 polymorphisms and environmental exposures related to farming lifestyle and to study the in vitro effects of lipopolysaccharide (LPS) stimulation on NPSR1 expression levels.
We studied 3113 children from PARSIFAL, a European cross-sectional study on environmental/lifestyle factors and childhood allergy, partly focused on children brought up on a farm. Information on exposures and outcomes was primarily obtained from parental questionnaires. Seven tagging polymorphisms were analysed in a conserved haplotype block of NPSR1. Multivariate logistic regression was used to evaluate a multiplicative model of interaction. NPSR1 protein and messenger RNA (mRNA) levels in monocytes were measured after LPS stimulation by fluorescence activated cell sorting (FACS) and quantitative real-time polymerase chain reaction (PCR).
A strong interaction was seen between current regular contact to farm animals and several NPSR1 polymorphisms, particularly rs323922 and rs324377 (p<0.005), with respect to allergic symptoms. Considering the timing of initiation of such current regular farm animal contact, significant interactions with these and two additional polymorphisms (SNP546333, rs740347) were revealed. In response to LPS, NPSR1-A protein levels in monocytes were upregulated (p = 0.002), as were NPSR1-A mRNA levels (p = 0.02).
The effect of farm animal contact on the development of allergic symptoms in children is modified by NPSR1 genetic background.
Journal of Medical Genetics 03/2008; 46(3):159-67. · 6.36 Impact Factor
-
Mauro D'Amato,
Sara Bruce,
Francesca Bresso,
Marco Zucchelli,
Sini Ezer, Ville Pulkkinen,
Cecilia Lindgren,
Marco Astegiano,
Mario Rizzetto,
Paolo Gionchetti, [......],
Pauli Puolakkainen,
Maarit Lappalainen,
Paulina Paavola-Sakki,
Leena Halme,
Martti Farkkila,
Ulla Turunen,
Kimmo Kontula,
Robert Lofberg,
Sven Pettersson,
Juha Kere
[show abstract]
[hide abstract]
ABSTRACT: The neuropeptide S receptor (NPSR1) gene has been associated recently with asthma and maps in a region of chromosome 7 previously linked also to inflammatory bowel disease (IBD). NPSR1 is expressed on the epithelia of several organs including the intestine, and appears to be up-regulated in inflammation. We tested NPSR1 gene polymorphism for association with IBD and verified whether the expression of its 2 major isoforms (NPSR1-A and NPSR1-B) is altered in the intestine of IBD patients.
Eight NPSR1 polymorphisms were genotyped in 2490 subjects from 3 cohorts of IBD patients and controls from Italy, Sweden, and Finland. Real-time polymerase chain reaction and immunohistochemistry were used to quantify NPSR1 messenger RNA (mRNA) and protein expression in intestinal biopsy specimens from IBD patients and controls.
Global analysis of the whole dataset identified strong association of a NPSR1 haplotype block with IBD (P = .0018) and its 2 major forms: Crohn's disease (CD) (P = .026) and ulcerative colitis (UC) (P = .003). Genetic effects caused by individual haplotypes were identified mainly for the predisposing haplotype H2 in CD (P = .0005) and the protective haplotype H8 in UC (P = .003). NPSR1 mRNA and protein levels were increased in IBD patients compared with controls, and the risk haplotype H2 correlated with higher expression of both NPSR1-A (P = .024) and NPSR1-B (P = .047) mRNAs.
NPSR1 polymorphism is associated with IBD susceptibility. Specific NPSR1 alleles might act as genetic risk factors for chronic inflammatory diseases of the epithelial barrier organs.
Gastroenterology 10/2007; 133(3):808-17. · 11.68 Impact Factor
-
Johanna Vendelin,
Sara Bruce,
Päivi Holopainen, Ville Pulkkinen,
Paula Rytilä,
Asta Pirskanen,
Marko Rehn,
Tarja Laitinen,
Lauri A Laitinen,
Tari Haahtela,
Ulpu Saarialho-Kere,
Annika Laitinen,
Juha Kere
[show abstract]
[hide abstract]
ABSTRACT: The neuropeptide S (NPS)-NPS receptor 1 (NPSR1) pathway has recently been implicated in the pathogenesis of asthma. The purpose of this study was to identify downstream gene targets regulated by NPSR1 upon NPS stimulation. A total of 104 genes were found significantly up-regulated and 42 down-regulated by microarray analysis 6 h after NPS administration. By Gene Ontology enrichment analysis, the categories 'cell proliferation', 'morphogenesis' and 'immune response' were among the most altered. A TMM microarray database comparison suggested a common co-regulated pathway, which includes JUN/FOS oncogene homologs, early growth response genes, nuclear receptor subfamily 4 members and dual specificity phosphatases. The expression of four up-regulated genes, matrix metallopeptidase 10 (MMP10), INHBA (activin A), interleukin 8 (IL8) and EPH receptor A2 (EPHA2), exhibited a significant NPS dose-response relationship as confirmed by quantitative reverse-transcriptase-PCR and for MMP10 by immunoassay. Immunohistochemical analyses revealed that MMP10 and TIMP metallopeptidase inhibitor 3 (TIMP3) were both strongly expressed in bronchial epithelium, and macrophages and eosinophils expressed MMP10 in asthmatic sputum samples. Because remodeling of airway epithelium is a feature of chronic asthma, the up-regulation of MMP10 and TIMP3 by NPS-NPSR1 signaling may be of relevance in the pathogenesis of asthma.
Human Molecular Genetics 11/2006; 15(19):2923-35. · 7.64 Impact Factor
-
Ulla Hodgson, Ville Pulkkinen,
Morag Dixon,
Myriam Peyrard-Janvid,
Marko Rehn,
Paivi Lahermo,
Vesa Ollikainen,
Kaisa Salmenkivi,
Vuokko Kinnula,
Juha Kere,
Pentti Tukiainen,
Tarja Laitinen
[show abstract]
[hide abstract]
ABSTRACT: We performed a genomewide scan in six multiplex families with familial idiopathic pulmonary fibrosis (IPF) who originated from southeastern Finland. The majority of the Finnish multiplex families were clustered in the region, and the population history suggested that the clustering might be explained by an ancestor shared among the patients. The genomewide scan identified five loci of interest. The hierarchical fine mapping in an extended data set with 24 families originating from the same geographic region revealed a shared 110 kb to 13 Mb haplotype on chromosome 4q31, which was significantly more frequent among the patients than in population-based controls (odds ratio 6.3; 95% CI 2.5-15.9; P = .0001). The shared haplotype harbored two functionally uncharacterized genes, ELMOD2 and LOC152586, of which only ELMOD2 was expressed in lung and showed significantly decreased messenger-RNA expression in IPF lung (n = 6) when compared with that of healthy lung (n = 7; P = .05). Our results suggest ELMOD2 as a novel candidate gene for susceptibility in familial IPF.
The American Journal of Human Genetics 08/2006; 79(1):149-54. · 10.60 Impact Factor
-
Ville Pulkkinen,
Marja-Leena Majuri,
Guoying Wang,
Päivi Holopainen,
Yasushi Obase,
Johanna Vendelin,
Henrik Wolff,
Paula Rytilä,
Lauri A Laitinen,
Tari Haahtela,
Tarja Laitinen,
Harri Alenius,
Juha Kere,
Marko Rehn
[show abstract]
[hide abstract]
ABSTRACT: G protein-coupled receptor 154 (GPR154) is a recently discovered asthma susceptibility gene upregulated in the airways of asthma patients. We previously observed increased pulmonary mRNA expression of the murine ortholog Gpr154 in a mouse model of ovalbumin (OVA)-induced inflammation. However, the expression profile of GPR154 in leukocytes and the cellular functions of the receptor and its endogenous agonist neuropeptide S (NPS) have remained unidentified. Here, we characterized the mRNA expression of NPS and GPR154 by using real-time RT-PCR in fractionated human blood cells and in peripheral blood mononuclear cells (PBMCs) with monocyte or T cell activation. The expression of GPR154 in leukocytes was further confirmed by immunoblotting experiments and immunohistochemical staining of human sputum samples. Additionally, we characterized the expression of GPR154 in the lung tissue samples and in the bronchoalveolar lavage (BAL) fluid of OVA sensitized and challenged BALB/c mice. In human blood and sputum cells, monocyte/macrophages and eosinophils were identified as GPR154-positive cells. In PBMCs, monocyte activation with LPS but not T cell activation with anti-CD3/CD28 antibodies resulted in increased NPS and GPR154 expression. In the lung tissue samples and in the BAL fluid of OVA-challenged mice, GPR154 expression was upregulated in alveolar macrophages in comparison to controls. In the mouse macrophage RAW 264.7 cell line, NPS-stimulated Galphas- and Galphaq-dependent phagocytosis of Escherichia coli. The results show that GPR154 is upregulated in macrophages after antigen challenge and that NPS is capable of inducing phagocytosis of unopsonized bacteria.
Human Molecular Genetics 06/2006; 15(10):1667-79. · 7.64 Impact Factor
-
Ville Pulkkinen,
Ritva Haataja,
Ulf Hannelius,
Otto Helve,
Olli M Pitkänen,
Riitta Karikoski,
Marko Rehn,
Riitta Marttila,
Cecilia M Lindgren,
Johanna Hästbacka,
Sture Andersson,
Juha Kere,
Mikko Hallman,
Tarja Laitinen
[show abstract]
[hide abstract]
ABSTRACT: Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) have some common features with asthma.
To study whether G protein-coupled receptor for asthma susceptibility (GPRA) contributes to RDS or BPD.
A haplotype association study was performed in a case-control setting of 521 Finnish infants (including 176 preterm neonates with RDS and 37 with BPD). Immunoreactivity of GPRA isoforms A and B was determined in pulmonary samples of fetuses, term infants and preterm infants with RDS or BPD. GPRA mRNA expression was determined by quantitative real-time polymerase chain reaction (PCR) in samples from nasal respiratory epithelium of adults, term infants and preterm infants.
In infants with RDS born at 32-35 weeks of gestation, GPRA haplotype H1 was significantly underrepresented in RDS, whereas haplotype H4/H5 was associated with an increased risk. As in asthma, GPRA B isoform was induced in bronchial smooth muscle cells in RDS and BPD. In nasal respiratory epithelium, relative GPRA mRNA expression was strong in adults, weak in preterm and slightly higher in term samples.
The results suggest that near-term RDS and asthma share the same susceptibility and protective GPRA haplotypes. Altered GPRA expression may play a role in the pathogenesis of RDS and BPD in preterm infants.
Annals of Medicine 02/2006; 38(5):357-66. · 3.52 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We recently identified a novel positional asthma susceptibility gene, GPRA, which belongs to the G protein-coupled receptor family. In the present studies, we show that isoform specific activation of GPRA-A with its agonist, Neuropeptide S (NPS) resulted in significant inhibition of cell growth. GPRA has several variants due to extensive alternative splicing. We observed that only the full-length variants, GPRA-A and GPRA-B, with 7 transmembrane topology are transported into the plasma membrane, while the truncated proteins retain intracellular compartments. To clarify disease mechanism, we studied co-expression of the variants without finding any indication that truncated variants would inhibit the receptor transport into the plasma membrane. By using in situ hybridization and immunohistochemistry, we detected ubiquitous expression of GPRA-B, and frequent expression of GPRA-A in the epithelia of several organs including bronchi and gastrointestinal tract. Furthermore, we observed aberrant mRNA and protein expression levels of GPRA in the asthmatic bronchi. Finally, we demonstrate that GPRA and NPS are co-expressed in bronchial epithelium. In summary, this study provides evidence that GPRA might have functional relevance in modulating asthma by increased expression levels in the relevant tissues under diseased state and by potential inhibitory effect of GPRA-A activation on cell growth.
American Journal of Respiratory Cell and Molecular Biology 10/2005; 33(3):262-70. · 5.13 Impact Factor
-
Tarja Laitinen,
Anne Polvi,
Pia Rydman,
Johanna Vendelin, Ville Pulkkinen,
Paula Salmikangas,
Siru Mäkelä,
Marko Rehn,
Asta Pirskanen,
Anna Rautanen, [......],
Harriet Gullstén,
Marina Leino,
Harri Alenius,
Tuula Petäys,
Tari Haahtela,
Annika Laitinen,
Catherine Laprise,
Thomas J Hudson,
Lauri A Laitinen,
Juha Kere
[show abstract]
[hide abstract]
ABSTRACT: Susceptibility to asthma depends on variation at an unknown number of genetic loci. To identify susceptibility genes on chromosome 7p, we adopted a hierarchical genotyping design, leading to the identification of a 133-kilobase risk-conferring segment containing two genes. One of these coded for an orphan G protein-coupled receptor named GPRA (G protein-coupled receptor for asthma susceptibility), which showed distinct distribution of protein isoforms between bronchial biopsies from healthy and asthmatic individuals. In three cohorts from Finland and Canada, single nucleotide polymorphism-tagged haplotypes associated with high serum immunoglobulin E or asthma. The murine ortholog of GPRA was up-regulated in a mouse model of ovalbumin-induced inflammation. Together, these data implicate GPRA in the pathogenesis of atopy and asthma.
Science 05/2004; 304(5668):300-4. · 31.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Insulin-like growth factors (IGFs) I and II are critical regulators of cell proliferation and differentiation and most of the growth promoting properties of both ligands are mediated by IGF-I receptor (IGF-IR). In the present study we have investigated the role of IGFs in K562 cell line during normal growth and 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced megakaryocytic differentiation. Abundant expression of IGF-I, IGF-II and IGF-IR was demonstrated in resting cells and exogenous IGF-I and IGF-II increased 3H-thymidine incorporation in a dose dependent manner. In contrast, we found that basal growth of the cells was inhibited by using anti-IGF-IR mAb. Furthermore, also IGF-I and IGF-II induced DNA synthesis was significantly suppressed by anti-IGF-IR mAb. During megakaryocytic differentiation, expression of IGF-IR increased during first 12h, but after that the expression started to decrease together with IGF-I. Taken together, our data suggest that autocrine production of IGF-I and IGF-II may via IGF-IR play a significant role in the growth and megakaryocytic differentiation of K562 cells.
Leukemia Research 10/2002; 26(9):831-7. · 2.92 Impact Factor
-
Ville. Pulkkinen
