Interferon-α, interferon-γ and sizofiran in the adjuvant therapy in ovarian cancer — a preliminary trial

The study included 24 cases of negative second-look laparotomy (SLL) after operation on ovarian cancer. 12 cases were treated with sizofiran and recombinant interferon-gamma before and after SLL and then with human lymphoblastoid interferon-alpha. The remaining 12 cases (controls) were followed up without any drug therapy after SLL. There were no recurrences in the treated group, but in 3 cases of the control group. Also significant difference in survival was noted in the treated group.     

Interleukin-1β signaling in osteoarthritis – chondrocytes in focus

Osteoarthritis (OA) can be regarded as a chronic, painful and degenerative disease that affects all tissues of a joint and one of the major endpoints being loss of articular cartilage. In most cases, OA is associated with a variable degree of synovial inflammation. A variety of different cell types including chondrocytes, synovial fibroblasts, adipocytes, osteoblasts and osteoclasts as well as stem and immune cells are involved in catabolic and inflammatory processes but also in attempts to counteract the cartilage loss. At the molecular level, these changes are regulated by a complex network of proteolytic enzymes, chemokines and cytokines (for review: [1]). Here, interleukin-1 signaling (IL-1) plays a central role and its effects on the different cell types involved in OA are discussed in this review with a special focus on the chondrocyte.     

Immunolocalization of latent transforming growth factor-ß binding protein-1 (LTBP1) during mouse development: possible roles in epithelial and mesenchymal cytodifferentiation

Latent transforming growth factor-β binding protein-1 (LTBP1) is a member of the fibrillin family; it is a glycoprotein of more than 190 kDa that is characterized by its possession of 16–18 epidermal growth factor-like motifs and 8 cysteine residues. The secretion of transforming growth factor-β involves its release from cells in a large latent complex containing LTBP1, a latency-associated peptide, and the mature region of the growth factor. Using a polyclonal antibody specific for LTBP1 (Ab39), we examined the immunohistochemical localization of this molecule during mouse embryogenesis between 8.5 and 13.5 embryonic days. An extracellular fibrillar structure containing LTBP1 was found in both the basement membrane of epithelia and mesenchymal tissue in which extensive tissue remodeling is carried out. Immunoelectron microscopy revealed Ab39 immunoreactivity on a 5- to 10-nm microfibrillar component of these basement membranes as well as in mesenchymal tissue. These results suggest that LTBP1 is one of the extracellular microfibrillar components of the basement membrane and of mesenchymal tissue, and that it may play an important role in the regulation of developmental phenomena involved in epithelial-mesenchymal interaction and epithelial differentiation, processes in which transforming growth factor-β is required for the control of cellular differentiation.     

Interleukin-1α-induced changes in chromium-51 absorption, tissue retention, and urinary excretion in rats

The effects of interleukin-1 alpha (IL-1α) on chromium-51 absorption, tissue retention, and urinary excretion were studied in adult male Sprague-Dawley rats. Ten rats were deprived of food for 12 h, injected intraperitoneally with mouse recombinant IL-1α (1 Μg/kg of body weight in phosphate-buffered saline [PBS]) or control (0.1% bovine serum albumin [BSA] in PBS). Two hours after dosing with the IL-1α, rats were fed 50 ΜL (200 ΜCi, 0.36 Μg Cr) of⁵¹CrCl₃ by micropipet. Blood was collected from the tail at 0.25, 0.5, 1, 2, and 4 h. Six hours after dosing with⁵¹CrCl₃, rats were exsanguinated and blood and tissues were sampled. The IL-lα significantly decreased chromium-51 in blood, urine, and some tissues compared to the control. The decreased absorption, retention, and urinary excretion of chromium-51 from⁵¹CrCl₃ in this study may be due to IL-1α-mediated increases in the production of prostaglandins and/or decreased production of gastric acid.     

Distinct roles of AKT isoforms in regulating β1-integrin activity, migration, and invasion in prostate cancer

AKT1 and AKT2 kinases have been shown to play opposite roles in breast cancer migration and invasion. In this study, an RNA interference screen for integrin activity inhibitors identified AKT1 as an inhibitor of β1-integrin activity in prostate cancer. Validation experiments investigating all three AKT isoforms demonstrated that, unlike in breast cancer, both AKT1 and AKT2 function as negative regulators of cell migration and invasion in PC3 prostate cancer cells. Down-regulation of AKT1 and AKT2, but not AKT3, induced activation of cell surface β1-integrins and enhanced adhesion, migration, and invasion. Silencing of AKT1 and AKT2 also resulted in increased focal adhesion size. Importantly, the mechanisms involved in integrin activity regulation were distinct for the two AKT isoforms. Silencing of AKT1 relieved feedback suppression of the expression and activity of several receptor tyrosine kinases, including EGFR and MET, with established cross-talk with β1-integrins. Silencing of AKT2, on the other hand, induced up-regulation of the microRNA-200 (miR-200) family, and overexpression of miR-200 was sufficient to induce integrin activity and cell migration in PC3 cells. Taken together, these data define an inhibitory role for both AKT1 and AKT2 in prostate cancer migration and invasion and highlight the cell type-specific actions of AKT kinases in the regulation of cell motility.     

RhoH plays distinct roles in T-cell migrations induced by different doses of SDF1α

Hematopoietic-specific RhoGTPase RhoH displays an important role in regulating T-cell development, a process that is accompanied by ordered and directed migration of progenitors through thymus. While RhoGTPases are key regulators of cytokinesis, the precise role of RhoH in T-cell migration is unknown. Here, by using Jurkat cell migration as a model, we found that RhoH is required for cell migration in response to the high concentration of SDF1α but displays inhibitory roles in regulating migration in the absence of SDF1α or in the range of low concentrations. We further found that RhoH-mediated migration requires PAK1 but not ITK. Indeed, both the low and high concentrations of SDF1α activate PAK1 but only the high concentration-induced activation of PAK1 requires RhoH. Further study of the RhoH–PAK interaction revealed that RhoH is able to bind and activate PAK1, indicating that RhoH plays a positive role in response to the high concentration of SDF1α. In contrast, at rest, RhoH indirectly inhibits Slp76/ITK activity through its modulation on TCR signaling, supporting a negative regulatory role for RhoH when SDF1α is insufficient to activate the RhoH–PAK1 pathway. Together, our study uncovered a dual role for RhoH in SDF1α signaling in T-cell responses.     

Biology of recently discovered cytokines: Interleukin-17 – a unique inflammatory cytokine with roles in bone biology and arthritis

IL-17 and its receptor are founding members of an emerging family of cytokines and receptors with many unique characteristics. IL-17 is produced primarily by T cells, particularly those of the memory compartment. In contrast, IL-17 receptor is ubiquitously expressed, making nearly all cells potential targets of IL-17. Although it has only limited homology to other cytokines, IL-17 exhibits proinflammatory properties similar to those of tumor necrosis factor-α, particularly with respect to induction of other inflammatory effectors. In addition, IL-17 synergizes potently with other cytokines, placing it in the center of the inflammatory network. Strikingly, IL-17 has been associated with several bone pathologies, most notably rheumatoid arthritis.