The chicken IL-1 family: evolution in the context of the studied vertebrate lineage

The interleukin-1 gene family encodes a group of related proteins that exhibit a remarkable pleiotropy in the context of health and disease. The set of indispensable functions they control suggests that these genes should be found in all eukaryotic species. The ligands and receptors of this family have been primarily characterised in man and mouse. The genomes of most non-mammalian animal species sequenced so far possess all of the IL-1 receptor genes found in mammals. Yet, strikingly, very few of the ligands are identifiable in non-mammalian genomes. Our recent identification of two further IL-1 ligands in the chicken warranted a critical reappraisal of the evolution of this vitally important cytokine family. This review presents substantial data gathered across multiple, divergent metazoan genomes to unambiguously trace the origin of these genes. With the hypothesis that all of these genes, both ligands and receptors, were formed in a single ancient ancestor, extensive database mining revealed sufficient evidence to confirm this. It therefore suggests that the emergence of mammals is unrelated to the expansion of the IL-1 family. A thorough review of this cytokine family in the chicken, the most extensively studied amongst non-mammalian species, is also presented. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00251-014-0780-7) contains supplementary material, which is available to authorized users

A dual role for the N-terminal domain of the IL-3 receptor in cell signalling

The interleukin-3 (IL-3) receptor is a cell-surface heterodimer that links the haemopoietic, vascular and immune systems and is overexpressed in acute and chronic myeloid leukaemia progenitor cells. It belongs to the type I cytokine receptor family in which the α-subunits consist of two fibronectin III-like domains that bind cytokine, and a third, evolutionarily unrelated and topologically conserved, N-terminal domain (NTD) with unknown function. Here we show by crystallography that, while the NTD of IL3Rα is highly mobile in the presence of IL-3, it becomes surprisingly rigid in the presence of IL-3 K116W. Mutagenesis, biochemical and functional studies show that the NTD of IL3Rα regulates IL-3 binding and signalling and reveal an unexpected role in preventing spontaneous receptor dimerisation. Our work identifies a dual role for the NTD in this cytokine receptor family, protecting against inappropriate signalling and dynamically regulating cytokine receptor binding and function.Sophie E. Broughton, Timothy R. Hercus, Tracy L. Nero, Winnie L. Kan ... Timothy P. Hughes, Angel F. Lopez ... et al

Levonorgestrel releasing intrauterine system (Mirena) versus endometrial ablation (Novasure) in women with heavy menstrual bleeding:a multicentre randomised controlled trial

<p>Background: Heavy menstrual bleeding is an important health problem. Two frequently used therapies are the levonorgestrel intra-uterine system (LNG-IUS) and endometrial ablation. The LNG-IUS can be applied easily by the general practitioner, which saves costs, but has considerable failure rates. As an alternative, endometrial ablation is also very effective, but this treatment has to be performed by a gynaecologist. Due to lack of direct comparison of LNG-IUS with endometrial ablation, there is no evidence based preferred advice for the use of one of these treatment possibilities.</p><p>Method/design: A multicenter randomised controlled trial, organised in a network infrastructure in the Netherlands in which general practitioners and gynaecologists collaborate.</p><p>Women >= 34 years with heavy menstrual bleeding, a Pictorial Blood Assessment Chart (PBAC) score exceeding 150 points and no future child wish can participate in the trial. After informed consent, women will be randomised to a strategy starting with a levonorgestrel releasing intrauterine system or a strategy starting with endometrial ablation.</p><p>The primary outcome is the PBAC score at 24 months of follow-up. Secondary outcomes are patient satisfaction, complications, number of re-interventions, menstrual bleeding pattern, quality of life, sexual function, sick leave and costs. As predictors of effect of intervention we also meaure level of coagulation factors.</p><p>Discusson: This study, considering both effectiveness and cost effectiveness of LNG-IUS versus endometrial ablation may well improve care for women with heavy menstrual bleeding.</p>