We have recently reported the presence and a potential proinflammatory role of IL-18 in the synovium of patients with rheumatoid arthritis. To obtain direct evidence that IL-18 plays an influential role in articular inflammation, we investigated the development of collagen-induced arthritis in a strain of mice lacking IL-18 (IL-18−/−) of DBA/1 background. IL-18−/− mice developed markedly reduced incidence of arthritis compared with heterozygous or wild-type mice. Of the IL-18−/− mice that developed arthritis, the severity of the disease was significantly reduced compared with the intact mice. This was accompanied by reduced articular inflammation and destruction evident on histology. IL-18−/− mice also had significantly reduced Ag-specific proliferation and proinflammatory cytokine (IFN-γ, TNF-α, IL-6, and IL-12) production by spleen and lymph node cells in response to bovine type II collagen (CII) in vitro compared with wild-type mice, paralleled in vivo by a significant reduction in serum anti-CII IgG2a Ab level. Treatment with rIL-18 completely reversed the disease of the IL-18−/− mice to that of the wild-type mice. These data directly demonstrate a pivotal role of IL-18 in the development of inflammatory arthritis and suggest that antagonists to IL-18 may have therapeutic potential in rheumatic diseases.

Enhanced endoglin expression is not limited to angiogenesis, it is also associated with inflammation.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Arthropods vary enormously in segment number, from less than 20 to more than 200. This between-species variation must have originated, in evolution, through divergent selection operating in ancestral arthropod species with variable segment numbers. Although most present-day arthropod species are invariant in this respect, some are variable and so can serve as model systems. Here, we describe a study based on one such species, the coastal geophilomorph centipede Strigamia maritima. We investigate the way in which segments are formed using in situ hybridization to demonstrate the expression pattern of the engrailed gene during embryogenesis. We also analyze segment number data in mother-offspring broods and thereby demonstrate a significant heritable component of the variation. We consider how natural selection might act on this intraspecific developmental variation, and we discuss the similarities and differences in segment formation between the geophilomorphs and their phylogenetic sister-group.

Summary:Hereditary hemorrhagic telangiectasia (HHT), associated with brain arteriovenous malformations, is caused by a loss of function mutation in either the endoglin (HHT1) or activin receptor-like kinase 1 gene (ALK-1, HHT2). Endoglin heterozygous (Eng +/− )mice have been proposed as a disease model. To better understand the role of endoglin in vascular malformation development, we examined the effect of vascular endothelial growth factor (VEGF) hyperstimulation on microvessels in adult endoglin heterozygous (Eng +/− ) mice using an adenoviral vector to deliver recombinant human VEGF 165 cDNA (AdhVEGF) into basal ganglia. VEGF expression was increased in AdhVEGF mice compared with the AdlacZ and saline group (P < 0.05) and localized to multiple cell types (neurons, astrocytes, endothelial cells, and smooth muscle cells) by double-labeled immunostaining. VEGF overexpression increased microvessel count for up to 4 weeks in both the Eng +/+ and Eng +/− groups (Eng +/+ 185 ± 14 vs. Eng +/− 201 ± 10 microvessels/mm 2 ). Confocal microscopic examination revealed grossly abnormal microvessels in eight of nine Eng +/− mouse brains compared with zero of nine in Eng +/+ mice (P < 0.05). Abnormal microvessels featured enlargement, clustering, twist, or spirals. VEGF receptor Flk-1 and TGF-␤ receptor 1 (T␤R1) expression were reduced in the Eng +/− mouse brain compared with control.Excessive VEGF stimulation may play a pivotal role in the initiation and development of brain vessel malformations in states of relative endoglin insufficiency in adulthood. These observations are relevant to our general understanding of the maintenance of vascular integrity.