Bases moleculares de la familia de la interleuquina-1 / Relevant aspects of the interleukin-1 family members

La interleuquina-1 (IL-1) es un miembro importante del grupo de las citoquinas pro inflamatorias. Pertenece a una superfamilia de citoquinas relacionadas que lleva su nombre, de las cuales se conocen tres agonistas (IL-la, IL-lp e IL-18) y un antagonista del receptor (IL-IRa). Las acciones biológicas de la IL-1 se basan en la inducción de genes que codifican para la ciclooxigenasa tipo 2 (COX2), la fosfolipasa A tipo 2 (PLAT2) y la óxido nítrico sintetasa inducible (iNOS). Las consecuencias biológicas de esta inducción se traducen en una franca respuesta inflamatoria. La IL-1 se une a dos receptores específicos, cuando lo hace con el receptor tipo I (IL-1RI) desencadena una vía de señalización intracelular que incluye la fosforilación proteica mediada por quinasas conocidas como IRAKs (quinasas asociadas al receptor de IL), y que es responsable de los efectos biológicos de la citoquinas. Por otro lado, la unión al receptor tipo II (IL-1RII) no desencadena ninguna señal. Los genes de la mayoría de los miembros de la familia de IL-1 se encuentran localizados en el brazo largo del cromosoma 2. Los loci polimórficos de estos genes parecen estar implicados en una amplia gama de enfermedades, aunque los resultados son motivo de controversia. En este artículo se tratan los aspectos más relevantes de los miembros de la familia de IL-1, desde el gen hasta la proteína, y su papel en la salud y en la enfermedad

Development and testing of new screening method for keratan sulfate in mucopolysaccharidosis IVA.

Mucopolysaccharidosis IVA (MPS IVA), a progressive lysosomal storage disease, causes skeletal dysplasia through excessive storage of keratan sulfate (KS). We developed an ELISA-sandwich assay that used a MAb specific to KS. Forty-five blood and 59 urine specimens from MPS IVA patients (ages 1-65 y) were analyzed to determine whether KS concentration is a suitable marker for early diagnosis and longitudinal assessment of disease severity. Blood specimens were obtained from patients categorized as phenotypically severe (n = 36) and milder (n = 9). Urine specimens were also analyzed from patients categorized as severe (n = 56) and milder (n = 12), respectively. Blood KS levels (101-1525 ng/mL) in MPS IVA patients were two to eight times higher than those in age-matched controls (15-323 ng/mL). It was found that blood KS level varied with age and clinical severity. Blood KS levels in both MPS IVA and controls peaked between 5 and 10 y of age (mean, 776 versus 234 ng/mL, respectively). Blood levels in severe MPS IVA were 1.5 times higher than in the milder form. In contrast to blood, urine KS levels in both MPS IVA and controls peaked between 1 and 5 y (15.3 versus 0.26 mg/g creatinine), and thereafter declined with age. Urine KS level also varied with age and clinical severity, and the severe MPS IVA phenotype was associated with 6.7 times greater urine KS excretion than the milder one. These findings indicate that the new assay for blood or urine KS may be suitable for early diagnosis and longitudinal assessment of disease severity in MPS IVA.

Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis.

Hereditary hemochromatosis (HH) is an autosomal recessive disease characterized by iron accumulation in several organs, followed by organ damage and failure. The C282Y mutation in the HFE gene explains 80-90% of all diagnosed cases of HH in populations of northwestern European ancestry. Targeted disruption of the mouse Hfe gene (or introduction of the murine mutation analogous to the C282Y human mutation) produces a murine model of HH. Another mutation in the HFE gene, H63D, is more prevalent than C282Y. However, the physiological consequences of the H63D mutation (as well as C282Y/H63D compound heterozygosity) on iron homeostasis are less well established. To evaluate the phenotypic consequences of the C282Y/H63D and H63D/H63D genotypes, we produced H67D (corresponding to H63D in humans) and C294Y (corresponding to C282Y in humans) knock-in mice. H67D homozygous mice, C294Y homozygous mice, and H67D/C294Y compound heterozygous mice each demonstrated hepatic iron loading. Even on a standard diet, by 10 weeks of age, hepatic iron levels in mice of these three genotypes were significantly higher than those of wild-type littermates. The relative severity of hepatic iron loading was C294Y/C294Y > C294Y/H67D > H67D/H67D. We conclude that the H67D allele, when homozygous or combined with a more consequential mutation like C294Y, leads to hepatic iron loading. These observations indicate that the H67D mutation leads to partial loss of Hfe function and can contribute to murine HH.