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1.
J Periodontal Res ; 43(1): 116-23, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18004991

RESUMEN

BACKGROUND AND OBJECTIVE: The gingival epithelium provides the first line of defense against colonization by periodontal pathogens, both as a physical barrier and by the production of inducible innate immune mediators such as beta-defensins and pro-inflammatory cytokines. The gram-negative bacterium Aggregatibacter actinomycetemcomitans is implicated in the pathogenesis of localized aggressive periodontitis, although the bacterium is found widely in the healthy population. We hypothesized that gingival epithelial cell-derived innate immune mediators triggered in response to A. actinomycetemcomitans infection may play an important role in increased susceptibility to infection. MATERIAL AND METHODS: Primary cultures of human gingival epithelial cells were cultured in the presence of A. actinomycetemcomitans. Total mRNA was examined for the presence of innate immune markers using RT-PCR. RESULTS: We show here that the mRNA levels of human beta-defensin 2 and interleukin-8 are elevated by live cultures of a clinical isolate of A. actinomycetemcomitans in cultured gingival epithelial cells from healthy individuals, but not by A. actinomycetemcomitans lipopolysaccharide. Cells from a patient with localized aggressive periodontitis, however, did not respond to this bacterial stimulation. In contrast, the pro-inflammatory cytokine interleukin-19 was induced in cells from both localized aggressive periodontitis and healthy subjects. Examination of Toll-like receptors and associated adapter molecules indicated lower levels of Toll-like receptor 2 mRNA in the localized aggressive periodontitis patient-derived cells compared with cells from healthy subjects. CONCLUSION: These results suggest that a differential expression of innate immune response genes to A. actinomycetemcomitans in the gingival epithelium could be an underlying factor of susceptibility to localized aggressive periodontitis.


Asunto(s)
Células Epiteliales/inmunología , Genes MHC Clase II/inmunología , Encía/citología , Pasteurellaceae/inmunología , Periodontitis/inmunología , Técnicas de Cultivo de Célula , Células Epiteliales/microbiología , Regulación Bacteriana de la Expresión Génica , Encía/inmunología , Encía/microbiología , Humanos , Interleucina-8/análisis , Periodontitis/genética , Periodontitis/microbiología , beta-Defensinas/análisis
2.
J Invest Dermatol ; 116(6): 975-8, 2001 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-11407990

RESUMEN

Beneficial effects of interleukin-10 therapy and lower endogenous interleukin-10 formation compared with atopic dermatitis and cutaneous T cell lymphomas indicated that interleukin-10 is a key cytokine in psoriasis. The interleukin-10 promoter is highly polymorphic, with two informative microsatellites, interleukin-10.G and interleukin-10.R. In order to understand whether interleukin-10 itself is a predisposing gene for the psoriasis susceptibility we analyzed interleukin-10 promotor polymorphism in patients. The distribution of interleukin-10.G and interleukin10.R microsatellite alleles did not vary between patients (n = 78) and healthy controls (n = 80). In addition, when the psoriasis patients were stratified according to age of onset (younger than 40 y of age, or age 40 and older), no difference in allele distribution was observed; however, a clear differential distribution was revealed at the interleukin10.G locus when patients were stratified according to whether they had a positive family history of psoriasis (p = 0.04). This difference was due to an over-representation of the interleukin10.G13 allele in those patients with familial disease (40.4% vs 19.6%, Chi-square = 7.292, p = 0.007). The positive association of allele interleukin10.G13 with familial psoriasis was especially true when patients with an early onset (< 40 y of age) of the disease were compared with those patients with early onset against a nonfamilial background (39.6% vs 14.5%, Chi-square = 8.959, p = 0.003). Patients with age-of-onset of less than 40 were 4-fold [odds ratio = 3.85 (1.55--9.62)] more likely to have a psoriatic family background if they carried this interleukin10.G13 allele. These data suggest that the interleukin-10 locus contributes to the heritability of psoriasis susceptibility.


Asunto(s)
Interleucina-10/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Psoriasis/genética , Alelos , Predisposición Genética a la Enfermedad , Humanos , Repeticiones de Microsatélite
3.
Genes Immun ; 8(2): 177-80, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17252004

RESUMEN

Interferon lambda-1 (IFN-lambda1), the prototype Type-III interferon, has antiviral functions similar to those of the Type-I interferons, IFN-alpha and IFN-beta. However, IFN-lambda1 is capable of signaling through almost all STAT molecules and so it is possible that it may have novel immunoregulatory functions in addition to antiviral ones. From a range of chemokines tested, IFN-lambda1 elevated mRNA levels of only 'Monokine induced by IFN-gamma' (MIG/CXCL9), 'IFN-gamma inducible protein-10' (IP-10/CXCL10) and 'IFN-gamma inducible T-cell alpha chemoattractant' (I-TAC/CXCL11) from human peripheral blood mononuclear cells. As their names suggest, these chemokines are also induced by IFN-gamma, the only member of the Type-II interferon family. This action of IFN-lambda1 did not depend on intermediate induction of IFN-gamma and is therefore, likely to be independent of IFN-gamma. Further, our results suggest that donors responded to IFN-lambda1 stimulation either 'early' or 'late'. Overall the action of IFN-lambda1 was similar to that previously reported for IFN-gamma and may invite more detailed investigation of the role of IFN-lambda1 at the innate/adaptive interface.


Asunto(s)
Quimiocinas CXC/metabolismo , Citocinas/metabolismo , Regulación de la Expresión Génica/genética , Interleucinas/metabolismo , ARN Mensajero/metabolismo , Quimiocinas CXC/genética , Cartilla de ADN , Humanos , Interferón gamma/metabolismo , Interferones , Leucocitos Mononucleares/metabolismo , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética
4.
Genes Immun ; 8(3): 254-61, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17361203

RESUMEN

Interferon lambda-1 (IFN-lambda1/IL-29) is a member of the Type-III interferon family, which contains three ligands: IFN-lambda1, 2 and 3. These three ligands use the same unique heterodimeric receptor composed of CRF2-12 (IFN-lambda-R1/IL-28Ralpha) and CRF2-4 (IL10-R-beta) chains. Like their close relatives, the Type-I interferons, IFN-lambda1, 2 and 3, promote the phosphorylation of STAT1 and STAT2, induce the ISRE3 complex, elevate OAS and MxA expression and exhibit antiviral activity in vitro. Their use of the IL10-R-beta chain and their ability to phosphorylate STAT3, STAT4 and STAT5 suggested that they may also exhibit immunomodulatory activity; their antiviral action led us to hypothesize that this activity might be directed toward the Th1/Th2 system. Here, we have demonstrated that IFN-lambda1 altered the activity of Th cells in three separate experimental systems: (i) mitogen stimulation, (ii) mixed-lymphocyte reaction (MLR) and (iii) stimulation of naive T cells by monocyte-derived dendritic cells (mDC). In Con-A stimulation assays, the inclusion of IFN-lambda1 consistently led to markedly diminished levels of secreted interleukin (IL-13) with occasional coincident, modest elevation of secreted IFN-gamma. IL-13 secretion was 100-fold more sensitive to IFN-lambda1 than was IFN-gamma secretion. These observations were also made in the allogeneic two-way MLR. IFN-lambda1 was able to alter cytokine-mediated Th biasing and when naive T cells were exposed to allogeneic mDC that had been matured in the presence of IFN-lambda1, secreted IL-13 was again markedly and consistently reduced, whereas secreted IFN-gamma was largely unaltered. These functions were independent of IL-10. Our data support a hitherto unsuspected role for IFN-lambda1 in modulating the development of Th1 and Th2 cells, with an apparent emphasis on the diminution of IL-13 secretion.


Asunto(s)
Citocinas/farmacología , Interleucinas/farmacología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Humanos , Técnicas In Vitro , Interferón gamma/biosíntesis , Interferones , Interleucina-10/antagonistas & inhibidores , Interleucina-13/biosíntesis , Isoantígenos , Prueba de Cultivo Mixto de Linfocitos , Proteínas Recombinantes/farmacología
5.
Genes Immun ; 8(1): 13-20, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17082759

RESUMEN

The interferon lambda family (IFN-lambda1/2/3) is a newly described group of cytokines that are related to both the type-1 interferons and IL-10 family members. These novel cytokines are induced during viral infection and, like type-1 interferons, display significant anti-viral activity. In order to understand their function in more depth, we have examined the ability of IFN-lambda1/IL-29 to regulate cytokine production by human immune cells. Whole peripheral blood mononuclear cells (PBMC) exposed to IFN-lambda1 specifically upregulated IL-6, -8 and -10 but there were no visible effects on TNF or IL-1. This response was produced in a dose-dependant fashion and was inhibited by IL-10. Examination of purified cell populations isolated from PBMC demonstrated that monocytes, rather than lymphocytes, were the major IFN-lambda1-responsive cellular subset, producing IL-6, -8 and -10 in response to IFN-lambda1. Monocyte responses induced by low-level LPS stimulation were also synergistically enhanced by the presence of IFN-lambda1. Human macrophages were also shown to react to IFN-lambda1 similarly to monocytes, by producing the cytokines IL-6, -8 and -10. In conclusion, we have shown that IFN-lambda1, a cytokine produced in response to viral infection, activates both monocytes and macrophages producing a restricted panel of cytokines and may therefore be important in activating innate immune responses at the site of viral infection.


Asunto(s)
Citocinas/biosíntesis , Interleucinas/inmunología , Leucocitos Mononucleares/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Linfocitos B/inmunología , Citocinas/inmunología , Relación Dosis-Respuesta Inmunológica , Humanos , Inmunidad Innata , Interferones , Lipopolisacáridos/inmunología , Linfocitos T/inmunología , Virus/inmunología
6.
Genes Immun ; 6(7): 632-5, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16208406

RESUMEN

Lactoferrin is an antimicrobial protein which plays an important role in regulating bacteria that are associated with aggressive periodontitis. Lactoferrin kills directly (via its strongly cationic N-terminal region) and indirectly, through sequestering the iron that bacteria require for growth. As aggressive periodontitis has a strong heritable component, we hypothesized that genetic variation within the lactoferrin gene may play a role in susceptibility to this condition. We have identified and examined a novel, functional, single-point A/G nucleotide mutation causing a threonine/alanine substitution at position 11 (T11A) of the secreted lactoferrin protein. In a pilot case-controlled study of aggressive periodontitis, analysis of 46 African-American patients and 78 controls showed that patients were twice as likely to express the G nucleotide (alanine) allele over controls (60.3 vs 30.4%; P=0.0007, odds ratio=2.564, 95% CI=1.475-4.459). A Caucasian population of 77 patients and 131 controls showed no such association (P=0.5201, odds ratio=0.862, 95% CI=0.548-1.356). The data presented provide a new insight into the genetic susceptibility to aggressive periodontitis.


Asunto(s)
Negro o Afroamericano/genética , Lactoferrina/genética , Periodontitis/genética , Polimorfismo de Nucleótido Simple , Alanina/genética , Sustitución de Aminoácidos , Estudios de Casos y Controles , Secuencia Conservada , Femenino , Humanos , Masculino , Periodontitis/etnología , Mutación Puntual , Treonina/genética , Población Blanca
7.
Genes Immun ; 1(7): 451-5, 2000 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11196676

RESUMEN

We have examined four polymorphic elements in the human interleukin-6 (IL-6) locus and described their allele distribution in 73 unrelated, healthy individuals from the West-of-Scotland. These comprised three single nucleotide polymorphisms (SNP) in the 5' promoter region of the gene and one VNTR in the 3' region of IL-6. A statistical consideration of the relationship between alleles at each locus was carried out. Of a total of 12 possible haplotypes observed in the population, the analysis suggested that four were prominent. These accounted for 41.1%, 28.1%, 14.4% and 3.4% respectively; in total, 87% of the haplotypes present. Frequently, these proposed haplotypes were supported by homozygosity across all four loci within individuals. We propose that these haplotypes be identified as IL6.0103, IL6.0204, IL6.0207 and IL6.0307, in recognition of their frequency in this population and the alleles that they contain.


Asunto(s)
Interleucina-6/genética , Alelos , Secuencia de Bases , ADN/genética , Frecuencia de los Genes , Haplotipos , Homocigoto , Humanos , Repeticiones de Minisatélite , Datos de Secuencia Molecular , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Escocia
8.
Immunogenetics ; 46(2): 120-8, 1997.
Artículo en Inglés | MEDLINE | ID: mdl-9162098

RESUMEN

Interleukin-10 (IL-10) is an important regulatory cytokine whose involvement extends into diverse areas of the human immune system. Recent characterization of the promoter and 5' flanking regions has demonstrated the presence of positive and negative regulatory segments in the promoter. In addition, the characterization of two dinucleotide repeat elements immediately upstream of the gene has shown that there is considerable polymorphism directly associated with the human IL10 gene. In the present report, we describe the mapping of the human IL10 gene to a discrete area of chromosome 1, the definition of a potential cytokine-responsive segment 3 - 4 kilobases upstream of the transcription initiation site, and the identification of two new point mutations in the immediate promoter region with their distribution in a panel of 75 unrelated healthy individuals. These data should further the understanding of how the IL10 gene is controlled in humans and how its function may vary between individuals.


Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 1 , Genoma Humano , Interleucina-10/genética , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Regiones Promotoras Genéticas/genética , Alineación de Secuencia , Análisis de Secuencia de ADN
9.
Genes Immun ; 1(2): 151-5, 1999 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11196662

RESUMEN

Interleukin-10 (IL-10) is a pivotal immunoregulatory cytokine, influencing many aspects of the immune response. The IL-10 gene is located on chromosome 1 at 1q31-32 and is highly polymorphic. One microsatellite and three single nucleotide polymorphisms (SNPs) have been recorded within the 1.2 kb immediately upstream of the gene, with an additional microsatellite present at 4 kb upstream. The relationship between these two classes of polymorphism is poorly defined in the IL-10 gene. Haplotypes have been presented comprising alleles from the two microsatellite loci, and independently from the three SNPs, but these have not yet been brought together to define unified halpotypes. In the present report we describe the 29 IL-10 haplotypes found in 56 Dutch European families and show that they fall into four major haplotype groups, each of which spans the 4 kb upstream of the IL-10 gene and has a different distribution of IL10.G alleles. In addition, we describe three novel single nucleotide polymorphisms in the human IL-10 gene and suggest how they relate to these four haplotype families.


Asunto(s)
Interleucina-10/genética , Repeticiones de Microsatélite/genética , Polimorfismo de Nucleótido Simple , Alelos , Citocinas/metabolismo , Haplotipos , Humanos , Países Bajos
10.
Tissue Antigens ; 49(6): 635-9, 1997 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9234486

RESUMEN

Recent studies have shown elevated IL-10 levels in several rheumatic autoimmune diseases, and particularly in systemic lupus erythematosus (SLE). Such changes may have a genetic basis. We studied two novel polymorphic dinucleotide repeats in the IL-10 promoter region (IL10.G and IL10.R) in order to investigate their possible significance in association with this condition in a group of 56 Caucasian SLE patients compared with 102 ethnically matched controls. The results show that there is an allelic imbalance between SLE patients and controls at the IL10.G microsatellite; this observation is supported by a significant difference in genotype distribution. The nature of autoantibody production and the presence or absence of renal involvement also appeared to be associated with certain IL10.G microsatellite alleles, although the small size of individual clinical sub-groupings may have influenced this result. No association with the IL10.R microsatellite was observed. Overall, the differences observed at the IL10.G microsatellite between SLE patients and controls suggest that the IL-10 locus contributes to the genetic background important for the development of this disease. Although the moderate sample size described in this study requires that the results be interpreted carefully, they provide an interesting and useful framework for future study.


Asunto(s)
Interleucina-10/genética , Lupus Eritematoso Sistémico/genética , Polimorfismo Genético , Alelos , Mapeo Cromosómico , Genotipo , Humanos , Datos de Secuencia Molecular
11.
Genes Immun ; 2(4): 181-90, 2001 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-11477472

RESUMEN

Interleukin-10 (IL-10) is an important immunoregulatory cytokine. The recent characterisation of the proximal 5' flanking region of IL-10 led to the identification of the promoter region. Two polymorphic dinucleotide repeats and 10 single nucleotide polymorphisms (SNPs) have been identified and suggested to be useful genetic markers in several diseases. We have sequenced a further 5275 bp from -9296 to -4021 of the distal part of the 5' flanking region of the human IL-10 gene from the cosmid clone pWE15-4/11. Our sequence analysis reveals a high density of Alu-repeats within the IL-10 gene locus, including three novel, related structures which we term Alu-IL10 (A-C). Using three overlapping PCR products spanning 5110 bp of this distal part of the IL-10 gene the following single base pair substitutions were identified: at -8571 C/T, -8531 G/A, -6752 A/T, -6208 G/C, -5402 C/G. In addition a heterozygous three base pair deletion at -7400 was observed. The SNPs at -8571 C/T and -8531 G/A are contained within an Alu-repeat. These data should further the understanding of how the IL-10 gene is controlled in man and how its function may vary between individuals.


Asunto(s)
Interleucina-10/genética , Secuencia de Bases , ADN , Humanos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Regiones Promotoras Genéticas , Secuencias Repetitivas de Ácidos Nucleicos , Homología de Secuencia de Ácido Nucleico , Factores de Transcripción/metabolismo
12.
J Periodontal Res ; 34(7): 379-86, 1999 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-10685365

RESUMEN

Early onset periodontitis (EOP) is considered to have a substantial genetic basis, although the gene or genes involved have not been elucidated. The aim of the present study was to investigate possible links between generalized EOP (GEOP) and genes regulating expression of the cytokines tumour necrosis factor (TNF) and interleukin-10 (IL-10). Microsatellite marker DNA sequences corresponding to phenotypic variations in cytokine response were analysed. Genotypic variations in cytokine response have been shown in vitro for TNF and IL-10, and specific alleles are implicated in diseases such as systemic lupus erythmatosus (SLE) and rheumatoid arthritis (RA). Two microsatellites at the IL-10 locus, IL10.R and IL10.G, and 1 microsatellite at the TNF locus, TNFa, were typed for 77 GEOP patients in the West of Scotland. Due to the highly polymorphic nature of the microsatellite loci, a statistical comparison with ethnically matched healthy controls (TNFa, n = 91, IL10.R, n = 94, IL10.G, n = 102) was conducted using a Monte Carlo simulation for each marker. No significant differences were observed for any of the 3 markers, although there were possible indications of trends similar to those observed in SLE for the IL10.G marker. In conclusion, no links were found between GEOP and microsatellites at TNFa, IL10.R or IL10.G loci.


Asunto(s)
Interleucina-10/genética , Periodontitis/inmunología , Polimorfismo Genético/genética , Factor de Necrosis Tumoral alfa/genética , Adulto , Periodontitis Agresiva/genética , Periodontitis Agresiva/inmunología , Alelos , Estudios de Casos y Controles , Mapeo Cromosómico , Regulación de la Expresión Génica , Ligamiento Genético/genética , Variación Genética/genética , Genotipo , Humanos , Repeticiones de Microsatélite/genética , Método de Montecarlo , Periodontitis/genética , Fenotipo , Análisis de Secuencia de ADN
13.
Genes Immun ; 1(3): 228-30, 2000 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11196717

RESUMEN

We provide characterization of a highly polymorphic dinucleotide repeat in the human TNF-receptor 1 gene (TNFR1, TNFRp55, CD120a). We have observed 11 alleles at this locus in individuals from the West of Scotland. In a panel of healthy, unrelated individuals from the West of Scotland (n = 143), the overall heterozygosity was 68%, indicating the potential usefulness of these markers in immunogenetic studies.


Asunto(s)
Antígenos CD/genética , Repeticiones de Microsatélite , Polimorfismo Genético , Receptores del Factor de Necrosis Tumoral/genética , Alelos , Secuencia de Bases , ADN/genética , Cartilla de ADN/genética , Repeticiones de Dinucleótido , Heterocigoto , Humanos , Datos de Secuencia Molecular , Receptores Tipo I de Factores de Necrosis Tumoral , Escocia
14.
Immunogenetics ; 45(3): 188-94, 1997.
Artículo en Inglés | MEDLINE | ID: mdl-8995185

RESUMEN

We examined the distribution of polymorphic elements within the tumor necrosis factor (TNF) gene cluster in 105 unrelated individuals and determined their relationship to class I and class II major histocompatibility complex (MHC) antigens, and to the highly polymorphic microsatellites TNFa and TNFb. The data demonstrate the contribution of elements within the TNF cluster to two extended haplotypes which are recognized to straddle the MHC. The A1.B8.DR3 haplotype appears to contain the TNF alleles TNFa2, TNFb3, LT.Nco-1.B*1, and TNF-308.2, while the A3.B7.DR2 haplotype is associated with the TNF alleles TNFa11, TNFb6, TNFc1, LT.Nco-1.B*2, LT.AspH1.1, TNF-308.1, and TNFe1. The presence of other extended associations which covered smaller parts of the MHC was also suggested. In most cases, the associations described here were in keeping with previously described extended haplotypes which dominate the structure of the MHC, but these did not always match completely. Taken together, these data suggest that the structure of the TNF locus is well integrated into the rest of the MHC but that important ethnic differences may exist.


Asunto(s)
Complejo Mayor de Histocompatibilidad , Familia de Multigenes , Polimorfismo Genético , Factor de Necrosis Tumoral alfa/genética , Estudios de Cohortes , Genes MHC Clase I , Genes MHC Clase II , Genotipo , Humanos , Linfotoxina-alfa/genética , Repeticiones de Microsatélite , Escocia
15.
Tissue Antigens ; 50(3): 303-7, 1997 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-9331953

RESUMEN

We examined six polymorphic elements in the tumor necrosis factor (TNF) locus and determined their allelic distribution in 98 Caucasian rheumatoid arthritis patients in comparison with 91 ethnically-matched controls. Polymorphic elements at four biallelic sites were distributed similarly between patients and controls, irrespective of the presence or absence of DR4. Differences were observed between the two groups at the TNFa and TNFe loci, but these were consistent with extended MHC haplotypes known to be present in rheumatoid arthritis patients. Therefore, this study suggests that there is little, if any, independent contribution of the TNF locus to the genetic background for rheumatoid arthritis susceptibility.


Asunto(s)
Artritis Reumatoide/genética , Polimorfismo Genético , Factor de Necrosis Tumoral alfa/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Mapeo Cromosómico , Genotipo , Humanos , Persona de Mediana Edad , Población Blanca/genética
16.
Proc Natl Acad Sci U S A ; 95(16): 9465-70, 1998 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-9689103

RESUMEN

Stimulation of human blood cultures with bacterial lipopolysaccharide (LPS) shows large inter-individual variation in interleukin 10 (IL-10) secretion, which has been shown to have a genetic component of over 70%. Alleles at two microsatellite loci in the 4 kb immediately upstream of the human IL-10 transcription initiation site in 132 individuals from 56 Dutch families were defined and assigned as haplotypes. LPS-induced IL-10 secretion was measured by ELISA and related to the IL-10 promoter haplotypes present in 78 unrelated individuals obtained from these families. Analysis showed that LPS-induced IL-10 secretion from unrelated individuals varied with IL-10 promoter haplotypes (P = 0.024; Kruskal-Wallis test). Two observations were made in relation to secreted IL-10 levels and promoter haplotypes; first, those haplotypes containing the allele IL10.R3 were associated with lower IL-10 secretion than haplotypes containing any other IL10.R allele. Second, the haplotype IL10.R2/IL10.G14 was associated with highest IL-10 secretion overall, whereas the haplotype IL10.R3/IL10.G7 was associated with lowest IL-10 secretion. These data demonstrate that the ability to secrete IL-10 can vary in man according to the genetic composition of the IL-10 locus.


Asunto(s)
Haplotipos , Interleucina-10/metabolismo , Alelos , Secuencia de Bases , Mapeo Cromosómico , Cartilla de ADN , Genotipo , Humanos , Interleucina-10/genética , Lipopolisacáridos/farmacología
17.
Eur J Biochem ; 78(1): 161-5, 1977 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-71990

RESUMEN

Complementary DNA (cDNA) was prepared with viral RNA-dependent DNA polymerase using human globin messenger RNA (mRNA) as template. By selective hydridization to globin mRNA from beta-thalassaemics a probe which was greater than 85% complementary to alpha-globin mRNA was purified. This was hybridized in cDNA excess to human genomic DNA, and the rate and extent of hybridization confirmed that there are two genes for alpha-globin per haploid genome. Cellular DNA was also prepared from peripheral blood from cases expressing the alpha-globin chain mutant Hb J Mexico to varying extents. This DNA was identical in hybridization behaviour to normal DNA demonstrating that the imbalanced mutant chain synthesis seen physiologically is not due to a gene deletion.


Asunto(s)
ADN/metabolismo , Genes , Globinas/biosíntesis , Hemoglobina A/biosíntesis , Hemoglobina J/genética , Hemoglobinas Anormales/genética , Hemoglobinas/biosíntesis , Adulto , Femenino , Haploidia , Humanos , Cinética , Hibridación de Ácido Nucleico , Placenta , Embarazo , ARN Mensajero/metabolismo , ADN Polimerasa Dirigida por ARN/metabolismo , Reticulocitos/metabolismo , Moldes Genéticos
18.
Genes Immun ; 1(7): 442-50, 2000 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11196675

RESUMEN

Interleukin-10 (IL-10) is a pleiotropic cytokine with important immunoregulatory functions whose actions influence activities of many of the cell-types in the immune system. We report here identification and cloning of a gene and corresponding cDNAs encoding a novel homologue of IL-10, designated IL-19. IL-19 shares 21% amino acid identity with IL-10. The exon/intron structure of IL-19 is similar to that of the human IL-10 gene, comprising five exons and four introns within the coding region of the IL-19 cDNA. There are at least two distinct IL-19 mRNA species that differ in their 5'-sequences, suggesting the existence of an intron in the 5'-sequences of coding portion of the IL-19 gene. The longer 5'-sequence contains an alternative initiating ATG codon that is in-frame with the rest of the coding sequence. The expression of IL-19 mRNA can be induced in monocytes by LPS-treatment. The appearance of IL-19 mRNA in LPS-stimulated monocytes was slightly delayed compared to expression of IL-10 mRNA: significant levels of IL-10 mRNA were detectable at 2 h post-stimulation, whereas IL-19 mRNA was not detectable until 4 h. Treatment of monocytes with IL-4 or IL-13 did not induce de novo expression of IL-19, but these cytokines did potentiate IL-19 gene expression in LPS-stimulated monocytes. In addition, GM-CSF was capable of directly inducing IL-19 gene expression in monocytes. IL-19 does not bind or signal through the canonical IL-10 receptor complex, suggesting existence of an IL-19 specific receptor complex, the identity of which remains to be discovered.


Asunto(s)
Interleucina-10/genética , Regiones no Traducidas 5' , Secuencia de Aminoácidos , Secuencia de Bases , Clonación Molecular , Cartilla de ADN/genética , ADN Complementario/genética , Humanos , Interleucinas , Datos de Secuencia Molecular , Monocitos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Homología de Secuencia de Aminoácido
19.
Tissue Antigens ; 50(1): 47-51, 1997 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9243755

RESUMEN

Independently, our two groups collaborating in this report performed association studies to consider the influence of the TNF region within the human MHC on the presence of colorectal cancer. In the Glasgow Study, 84 colorectal cancer patients were compared with 91 controls at the TNFa microsatellite locus. Analysis of individual alleles by Fisher's exact test revealed a significant overrepresentation of the TNFa2 allele in the colorectal cancer group, after correcting for multiple comparisons. In the Essen Study, 47 colorectal cancer patients were compared with 117 matched controls, and the hypothesis of TNFa2 overrepresentation in colorectal cancer was confirmed. These data provide evidence for the involvement of the TNF locus in the pathogenetic etiology of colorectal cancer.


Asunto(s)
Alelos , Neoplasias Colorrectales/genética , Repeticiones de Microsatélite , Factor de Necrosis Tumoral alfa/genética , Humanos
20.
Diabetes Metab Res Rev ; 16(4): 276-80, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-10934456

RESUMEN

BACKGROUND: Several Type 1 diabetes susceptibility loci have been located to chromosome 2q12-21. However, results have not always been consistent and this may reflect study design and the population analysed. We have used a family-based design to look for an association between Type 1 diabetes and markers located to 2q12-21. METHODS: Ninety-one South Indian families consisting of subjects with Type 1 diabetes and their parents were genotyped for eight polymorphic markers localised to 2q12-21, which includes the interleukin-1 gene cluster. Radiation hybrid mapping was used to localise the map position of D2S308 and D2S363 on 2q12-21. The extended transmission disequilibrium test was used for statistical analysis. RESULTS: No associations were found between Type 1 diabetes and markers located in and around the interleukin-1 gene cluster or the interleukin-1 Type 1 receptor. In contrast, a suggestive association was found between Type 1 diabetes and two closely-linked markers telomeric of the interleukin-1 gene cluster (D2S308 and D2S363, separated by 3.3 cR) (p=0.004 and p=0.002, respectively). CONCLUSION: This preliminary study suggests that a locus close to D2S308 and D2S363 is involved in the aetiology of Type 1 diabetes in the South Indian population.


Asunto(s)
Cromosomas Humanos Par 2 , Diabetes Mellitus Tipo 1/genética , Interleucina-1/genética , Adolescente , Adulto , Edad de Inicio , Mapeo Cromosómico , Diabetes Mellitus Tipo 1/inmunología , Femenino , Marcadores Genéticos , Humanos , India , Desequilibrio de Ligamiento , Masculino , Familia de Multigenes
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