SUMMARYThe genetic backgrounds of lupus-prone murine models are a valuable resource for studying the influence of environmental exposure on autoimmune diseases in sensitive populations. Epidemiological studies have shown associations between silica exposure and several autoimmune diseases, including scleroderma and systemic lupus erythematosus. To determine whether silica exposure can exacerbate systemic autoimmunity in genetically predisposed animals, New Zealand mixed mice were intranasally instilled twice with saline or saline suspensions of 1 mg silica or 500 m g TiO 2 , a dose equivalent in surface area, and were evaluated with respect to health and immune status. Survival in silica exposed NZM mice was decreased compared to saline and TiO 2 exposed mice. Proteinuria levels were elevated in silica exposed mice. Levels of circulating immune complexes, autoantibodies to nuclear antigen (ANA), histone, and double stranded DNA were measured every two weeks by ELISA. Circulating immune complexes showed a trend towards an increased acceleration in levels in the silica exposed mice compared to saline and TiO 2 exposed mice. ANA levels were significantly higher in silica exposed animals compared to saline and TiO 2 exposed animals (0·237 ± 0·03 versus 0·140 ± 0·029 and 0·125 ± 0·03, P < 0·05) 16 weeks postexposure. Autoantibodies to histone were also significantly elevated after 16 weeks in silica exposed animals compared to saline and TiO 2 exposed animals (0·227 ± 0·03 versus 0·073 ± 0·015 and 0·05 ± 0·03, P < 0·05). In contrast, serum IgG levels were decreased in silica exposed NZM mice compared to the saline controls, however, IgM levels were unaffected. Lungs of the silica-exposed mice had increased inflammatory infiltrates as well as fibrotic lesions characterized by excess collagen deposition. Therefore, although NZM mice are susceptible to SLE, silica exposure significantly exacerbated the course of disease.

Metastatic prostate cancer cells display EphB receptor-mediated attraction when they contact stromal fibroblasts but EphA-driven repulsion when they contact one another. The impact of these ‘social’ interactions between cells during cancer cell invasion and the signalling mechanisms downstream of Eph receptors are unclear. Here we show that EphA receptors regulate prostate cancer cell dissemination in a 2D dispersal assay and in a 3D cancer cell spheroid assay. We show that EphA receptors signal via the exchange factor Vav2 to activate RhoA and that both Vav2 and RhoA are required for prostate cancer cell–cell repulsion. Furthermore, we find that in EphA2/EphA4, Vav2 or RhoA siRNA-treated cells, contact repulsion can be restored by partial microtubule destabilisation. We propose that EphA–Vav2–RhoA-mediated repulsion between contacting cancer cells at the tumour edge could enhance their local invasion away from the primary tumour.

. Environmental oxygen tension affects phenotype in cultured bone marrow-derived macrophages. Am J Physiol Lung Cell Mol Physiol 286: L354-L362, 2004. First published October 3, 2003 10.1152/ajplung.00380.2002This study tested the hypothesis that the unique phenotype of alveolar macrophages (AM) is maintained through adaptation to the relatively high oxygen partial pressure (PO 2) of the lung, through modification of redox-sensitive transcription factors. BALB/c mouse bone marrowderived macrophages (BMC) were differentiated under different PO 2 and compared functionally to AM and peritoneal macrophages (PM). BMC differentiated in normoxia (PO 2 140 Torr, BMChigh) were similar to AM in having low phagocytic and antigen presenting cell (APC) activities. However, BMC grown in low oxygen tension as found in other tissues (Ͻ40 Torr, BMC low) were better phagocytes and APCs, similar to PM. BMC high were more oxidative intracellularly than BMC low, based on oxidation of dichlorofluorescein and higher glutathione disulfide/glutathione (GSH) ratios, despite having more GSH. Finally, lipopolysaccharide-induced nuclear factor-B translocation, measured by laser scanning cytometry, was reduced in BMC high and AM, compared with BMClow and PM, respectively. These data suggest that regulation of the AM phenotype may occur, at least in part, via inhibition of NF-B by the unique redox environment.redox; alveolar macrophage; glutathione; nuclear factor-B