RESUMEN
Psoriasis vulgaris is a genetically heterogenous disease with unclear molecular background. We assessed the association of psoriasis and its main clinical phenotypes with common variants of three potential psoriasis susceptibility genes: ZNF750, RPTOR and TRAF31P2. We genotyped 10 common variants in a cohort of 1,034 case-control individuals using Taqman genotyping assays and sequencing. Minor alleles of all four TRAF3IP2 variants were more frequent among cases. The strongest, significant association was observed for rs33980500 (OR = 2.5, p = 0.01790). Minor allele of this SNP was always present in two haplotypes found to be associated with increased psoriasis risk: rs13196377_G + rs13190932_G + rs33980500_T + rs13210247_A (OR = 2.7, p = 0.0054) and rs13196377_A + rs13190932_A + rs33980500_T + rs13210247_G (OR = 1.8, p = 0.0008). Analyses of clinically relevant phenotypes revealed association of rs33980500 with pustular psoriasis (OR = 1.2, p = 0.0109). We observed significant connection of severity of cutaneous disease with variation at rs13190932 and suggestive with three remaining TRAF3IP2 SNPs. Another positive associations were found between age of onset and familial aggregation of disease: smoking and younger age of onset, smoking and occurrence of pustular psoriasis, nail involvement and arthropatic psoriasis, nail involvement and more severe course of psoriasis. We found no statistically significant differences in the prevalence of the examined variants of RPTOR and ZNF750 genes among our cases and controls. We have replicated the association of TRAF3IP2-_rs33980500 variant with the susceptibility to psoriasis. We have found new associations with clinically relevant subphenotypes such as pustular psoriasis or moderate-to-severe cases. We ascertain no connection of RPTOR and ZNF750 variants with psoriasis or its subphenotypes.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Polimorfismo de Nucleótido Simple , Psoriasis/genética , Factores de Transcripción/genética , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/genética , Adulto , Edad de Inicio , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Desequilibrio de Ligamiento , Modelos Logísticos , Masculino , Análisis Multivariante , Oportunidad Relativa , Fenotipo , Modelos de Riesgos Proporcionales , Psoriasis/diagnóstico , Proteína Reguladora Asociada a mTOR , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Proteínas Supresoras de TumorRESUMEN
Hematopoiesis is regulated by components of the microenvironment, so-called niche. Here, we show that p190-B GTPase-activating protein (p190-B) deletion in mice causes hematopoietic failure during ontogeny, in p190-B(-/-) fetal liver and bones, and in p190-B(+/-) adult bones and spleen. These defects are non-cell autonomous, as we previously showed that transplantation of p190-B(-/-) hematopoietic cells into wild-type (WT) hosts leads to normal hematopoiesis. Coculture of mesenchymal stem (MSC)/progenitor cells and wild-type bone marrow (BM) cells reveals that p190-B(-/-) MSCs are dysfunctional in supporting hematopoiesis owing to impaired Wnt signaling. Furthermore, p190-B loss causes alteration in BM niche composition, including abnormal colony-forming unit (CFU)-fibroblast, CFU-adipocyte and CFU-osteoblast numbers. This is due to altered MSC lineage fate specification to osteoblast and adipocyte lineages. Thus, p190-B organizes a functional mesenchymal/microenvironment for normal hematopoiesis during development.
Asunto(s)
Adipocitos/citología , Células de la Médula Ósea/citología , Microambiente Celular , Proteínas Activadoras de GTPasa/fisiología , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/citología , Células Madre Mesenquimatosas/citología , Adipocitos/metabolismo , Animales , Células de la Médula Ósea/metabolismo , Huesos/citología , Huesos/metabolismo , Diferenciación Celular , Células Cultivadas , Feto , Fibroblastos/citología , Fibroblastos/metabolismo , Citometría de Flujo , Células Madre Hematopoyéticas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osteoblastos/citología , Osteoblastos/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Bazo/citología , Bazo/metabolismo , Células Madre , Células del Estroma/citología , Células del Estroma/metabolismo , Proteínas Wnt/metabolismoRESUMEN
Xeroderma pigmentosum is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. The presence of a distinct the nucleotide excision repair (NER) mutation signature in melanoma suggests that perturbations in this critical repair process are likely to be involved with disease risk. We hypothesized that persons with polymorphic NER gene(s) are likely to have reduced NER activity and are consequently at an increased risk of melanoma development. We assessed the association between 94 SNPs within seven XP genes (XPA-XPG) and the melanoma risk in the Polish population. We genotyped 714 unselected melanoma patients and 1,841 healthy adults to determine if there were any polymorphisms differentially represented in the disease group. We found that a significantly decreased risk of melanoma was associated with the Xeroderma pigmentosum complementation (XPC) rs2228000_CT genotype (odds ratio [OR] = 0.15; p < 0.001) and the rs2228000_TT genotype (OR = 0.11; p < 0.001) compared to the reference genotype. Haplotype analysis within XPC revealed the rs2228001_A + G1475A_G + G2061A_A + rs2228000_T + rs3731062_C haplotype (OR = 0.26; p < 0.05) was associated with a significantly decreased disease risk. The haplotype analysis within the Xeroderma pigmentosum group D (XPD) showed a modest association between two haplotypes and a decrease in melanoma risk. There were no major differences between the prevalence of the XP polymorphisms among young or older patients with melanoma. Linkage disequilibrium of XPC: rs2228001, G1475A, G2061A, rs2228000 and rs3731062 was found. The data from our study support the notion that only XPC and XPD genes are associated with melanoma susceptibility.
Asunto(s)
Proteínas de Unión al ADN/genética , Melanoma/genética , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Xerodermia Pigmentosa/genética , Anciano , Reparación del ADN , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , RiesgoRESUMEN
Burn patients often experience a devastating inflammatory response to infection within the first two weeks after thermal injury. The inflammatory cytokines IL-6, TNF and IL-1 have been implicated in this condition but most studies have focused on the abnormal levels of cytokines in the plasma. In this study the production of cytokines was compared for Kupffer cells versus splenic macrophages; endotoxin (LPS) stimulation versus no stimulation; and burn (post burn days 1, 3 and 8) versus no burn (control). Corresponding serum levels of IL-6 were also determined. Kupffer cells from normal or burned animals were shown to produce much higher amounts of the inflammatory cytokines than that produced by splenic macrophages. An exception to this was the equal production of TNF by LPS-stimulated hepatic and splenic cells. Both LPS-stimulated Kupffer cells and splenic macrophages produced larger amounts of the cytokines than that produced by the unstimulated cells. There was a significant effect of thermal injury on cytokine production by LPS-stimulated Kupffer cells at post burn day 8 and on TNF production by stimulated splenic macrophages also at post burn day eight. Although there was a statistically significant effect of thermal injury at post burn day 8 on IL-1 production by unstimulated splenic macrophages, the absolute amount of cytokine produced was very small. The results suggest that by post burn day 8 the cells may have become primed to respond to a stimulus such as endotoxin (LPS), a condition that could arise in a burn patient from sepsis. Strangely, the large spike in serum IL-6 level occurred at post burn day one and the level of the cytokine returned nearly to the control value on post burn days 3 and 8.
Asunto(s)
Quemaduras/metabolismo , Citocinas/biosíntesis , Mediadores de Inflamación/metabolismo , Macrófagos del Hígado/metabolismo , Macrófagos/metabolismo , Bazo/metabolismo , Animales , Células Cultivadas , Endotoxinas/farmacología , Interleucina-1/biosíntesis , Interleucina-6/biosíntesis , Interleucina-6/sangre , Ratas , Ratas Sprague-Dawley , Bazo/patología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Kupffer cells and alveolar, splenic, and peritoneal macrophages from normal rats were incubated for various periods of time in the presence of LPS, and the culture supernatants were analyzed for IL-6, IL-1, and TNF. There was very little difference in the amounts of the cytokines produced by the macrophages when stimulated with 0.01-10 micrograms/ml of LPS. The shapes of the time course curves for the production of the cytokines by the different types of macrophages were generally similar, although only Kupffer cells continued to produce IL-6 throughout the entire incubation period and splenic macrophages showed a lag period in the production of IL-1. Kupffer cells produced more IL-6 than that produced by the other populations of macrophages, and alveolar macrophages produced more IL-1 compared to that produced by splenic cells. Kupffer cells and peritoneal macrophages produced more IL-6 in 24 h than in 6 h of culture, and splenic macrophages produced more IL-1 in 24 compared to 6 h of culture. Alveolar macrophages produced more TNF than that produced by the other populations of cells but only when integrated over the entire incubation period. These results confirm and extend the observed functional heterogeneity of macrophages obtained from different tissues of the same animal. This study and future studies will lead to a better understanding of the role of cytokines in the inflammatory response.
Asunto(s)
Interleucina-1/biosíntesis , Interleucina-6/biosíntesis , Macrófagos/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Línea Celular , Macrófagos del Hígado/metabolismo , Células L , Macrófagos Alveolares/metabolismo , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Endogámicos C3H , Bazo/citología , Linfocitos TRESUMEN
The effect of thermal injury on the in vitro production of TNF, IL-6, and PGE2 by bone marrow-derived, LPS-stimulated rat macrophages was studied. Thermal injury caused a general hyperactivity in the production of the mediators by the cells. Indomethacin, a cyclooxygenase inhibitor of PGE2 synthesis, inhibited the production of IL-6 and PGE2 but had no effect on the production of TNF. These results suggest that the observed low concentration of PGE2 produced by the cells was insufficient to cause inhibition of TNF synthesis; thus, the effect of indomethacin would be undetectable. The results also suggest that indomethacin may act directly in inhibiting the production of IL-6 by the macrophages. The hyperactive effect of thermal injury on the production of inflammatory mediators by newly differentiated bone marrow derived macrophages can be important in the overall systemic response to the insult.
Asunto(s)
Médula Ósea/metabolismo , Quemaduras/metabolismo , Citocinas/biosíntesis , Dinoprostona/biosíntesis , Lipopolisacáridos/farmacología , Macrófagos/metabolismo , Animales , Células de la Médula Ósea , Indometacina/farmacología , Interleucina-6/biosíntesis , Masculino , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
The relationship of translocation of bacteria from the gut of burned guinea pigs and the in vitro production of tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6, and prostaglandin E2 (PGE2) by lipopolysaccharide (LPS)-stimulated mesenteric lymph node and splenic macrophages was investigated at two early times after thermal injury. Two hr postburn, there was a large number of translocated bacteria in the mesenteric lymph nodes and a large proportion was killed; at 24 hr postburn, there were fewer translocated bacteria, but a large proportion was viable. In some cases, there were very large differences compared to controls in the amounts of TNF, IL-6, and PGE2, but not of IL-1, produced by the macrophages at different times postburn and at different in vitro incubation times. The results suggest that the macrophages were primed by the burn or the translocated bacteria to produce in vitro different and sometimes large amounts of cytokines or PGE2 after further stimulation with LPS. Although there was no direct correlation between production of cytokines or PGE2 and time postburn, the early increased production of PGE2 by splenic macrophages could have depressed the animal's ability to kill translocated bacteria by 24 hr postburn, and could be one of the mechanisms of the cause of systemic infection after burn injury.