This study characterizes the mRNA profile of the IL-17 isoforms and receptors in psoriatic skin lesions. Furthermore, we demonstrate for the first time augmented protein levels of IL-17A, IL-17C and IL-17F in psoriatic skin lesions, indicating a possible role for IL-17C in addition to IL-17A and IL-17F in the pathogenesis of psoriasis.

IntroductionRheumatoid arthritis (RA) is a chronic progressive, inflammatory and destructive autoimmune disease, characterised by synovial joint inflammation and bone erosion. To better understand the pathophysiology and underlying immune mechanisms of RA various models of arthritis have been developed in different inbred strains of mice. Establishment of arthritis models with components of adaptive immunity in the C57BL/6J strain of mice has been difficult, and since most genetically modified mice are commonly bred on this background, there is a need to explore new ways of obtaining robust models of arthritis in this strain. This study was undertaken to establish and characterise a novel murine model of arthritis, the delayed-type hypersensitivity (DTH)-arthritis model, and evaluate whether disease can be treated with compounds currently used in the treatment of RA.MethodsDTH-arthritis was induced by eliciting a classical DTH reaction in one paw with methylated bovine serum albumin (mBSA), with the modification that a cocktail of type II collagen monoclonal antibodies was administered between the immunisation and challenge steps. Involved cell subsets and inflammatory mediators were analysed, and tissue sections evaluated histopathologically. Disease was treated prophylactically and therapeutically with compounds used in the treatment of RA.ResultsWe demonstrate that DTH-arthritis could be induced in C57BL/6 mice with paw swelling lasting for at least 28 days and that disease induction was dependent on CD4+ cells. We show that macrophages and neutrophils were heavily involved in the observed pathology and that a clear profile of inflammatory mediators associated with these cell subsets was induced locally. In addition, inflammatory markers were observed systemically. Furthermore, we demonstrate that disease could be both prevented and treated.ConclusionsOur findings indicate that DTH-arthritis shares features with both collagen-induced arthritis (CIA) and human RA. DTH-arthritis is dependent on CD4+ cells for induction and can be successfully treated with TNFα-blocking biologics and dexamethasone. On the basis of our findings we believe that the DTH-arthritis model could hold potential in the preclinical screening of novel drugs targeting RA. The model is highly reproducible and has a high incidence rate with synchronised onset and progression, which strengthens its potential.

The plasminogen activation (PA) cascade participates in degradation of extracellular matrix during cancer invasion. We have studied the expression of urokinase-type plasminogen activator (uPA) mRNA, uPA receptor (uPAR) mRNA and immunoreactivity, and type-1 plasminogen activator inhibitor (PAI-1) mRNA and immunoreactivity in 16 prostate adenocarcinomas and 9 benign prostate hyperplasias. uPA mRNA and uPAR mRNA expression were found in 9 and 8 of the adenocarcinomas, respectively, and in 7 and 6 of the benign hyperplasias, respectively. In both malignant and benign lesions, expression of these 2 mRNAs was predominantly seen in cells identified as macrophages, which in most of the carcinomas (ϳ90%) were located in the interstitial tissue between the tumor cell islands, while in most of the benign hyperplasias they were located in the lumen of the glands and were in only a few cases (ϳ30%) found in the interstitial tissue. uPAR immunoreactivity correlated with the mRNA expression and was, in addition, found in neutrophils. PAI-1 mRNA was detected in 13 of the 16 carcinomas and in 8 of the 9 benign hyperplasias, located in scattered fibroblast-like cells in both groups, in some vascular structures and in a few macrophages located in the interstitial tissue of both malignant and benign lesions. A similar expression pattern was found for PAI-1 immunoreactivity. In 8 of the 16 carcinomas, all 3 components were present, and in several areas colocalization was observed in stromal cells in close proximity to cancer cell islands. No immunoreactivity and/or mRNA expression of uPA, uPAR or PAI-1 was observed in cancer cells or in other epithelial cells in any of the cases.

Urokinase plasminogen activator (uPA) and its receptor (uPAR) coordinate a plasmin-mediated proteolytic cascade that has been implicated in cell adhesion, cell motility, and matrix breakdown, for example, during inflammation. As part of their function during inflammatory responses, macrophages move through tissues and encounter both two-dimensional (2D) surfaces and more complex three-dimensional (3D) interstitial matrices. Based on approaches employing uPA gene–deficient macrophages, plasminogen supplementation, and neutralization with specific protease inhibitors, it is reported in this study that uPA activity is a central component of the invasion of macrophages through a 3D Matrigel barrier; it also has a nonredundant role in macrophage-mediated matrix degradation. For murine macrophages, matrix metalloproteinase-9 activity was found to be required for these uPA-mediated effects. Evidence for a unique role for uPA in the inverse relationship between macrophage adhesion and 2D migration was also noted: macrophage adhesion to vitronectin was enhanced by uPA and blocked by plasminogen activator inhibitor-1, the latter approach also able to enhance in turn the 2D migration on this matrix protein. It is therefore proposed that uPA can have a key role in the inflammatory response at several levels as a central regulator of macrophage 3D invasion, matrix remodeling, and adhesion.

We have developed a computer-assisted stereological method based on unbiased principles for estimating metastasis volumes in mouse lungs. We evaluated this method using the transplantable Lewis lung carcinoma. Twenty-one days after subcutaneous inoculation of 10(6) Lewis lung cells into C57BL/6J mice, the mice had primary tumors with an average volume of 2300 mm(3). After perfusion fixation, the lungs were removed, embedded in OCT compound, snap-frozen, and processed for stereology. The metastasis volumes were estimated by application of the Cavalieri principle after evaluation of single sections from several evenly distributed tissue levels. The metastasis volume in a group of nine mice varied between 0.01 and 14.4 mm(3), with an average of 6.1 mm(3). The coefficient of variation was 0.9. The coefficient of error of the volume estimation was determined in five cases and varied from 0.08 to 0.23. Thus, the variation on the metastasis volumes that is achieved by this method contributes very little, 2.5%, to the total variance within the group of mice. In conclusion, we have developed an efficient and unbiased method to determine the metastasis burden in mouse lungs.