There is a growing interest in the targeting of Toll-like receptors (TLRs) for the prevention and treatment of cancer, rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus (SLE). Several new compounds are now undergoing preclinical and clinical evaluation, with a particular focus on TLR7 and TLR9 activators as adjuvants in infection and cancer, and inhibitors of TLR2, TLR4, TLR7 and TLR9 for the treatment of sepsis and inflammatory diseases. Here, we focus on TLRs that hold the most promise for drug discovery research, highlighting agents that are in the discovery phase and in clinical trials,and on the emerging new aspects of TLR-mediated signalling - such as control by ubiquitination and regulation by microRNAs - that might offer further possibilities of therapeutic manipulation.

Objective. To profile the expression of all known members of the matrix metalloproteinase (MMP), ADAMTS, and tissue inhibitor of metalloproteinases (TIMP) gene families in normal cartilage and cartilage from patients with osteoarthritis (OA).Methods. Human cartilage was obtained from femoral heads at joint replacement for OA or following fracture to the femoral neck. Total RNA was purified, and gene expression was assayed using quantitative real-time polymerase chain reaction.Results. Several members of the above gene families were regulated in OA. Genes that showed increased expression in OA were MMP13, MMP28, and ADAMTS16 (all at P < 0.001), MMP9, MMP16, ADAMTS2, and ADAMTS14 (all at P < 0.01), and MMP2, TIMP3, and ADAMTS12 (all at P < 0.05). Genes with decreased expression in OA were MMP1, MMP3, and ADAMTS1 (all at P < 0.001), MMP10, TIMP1, and ADAMTS9 (all at P < 0.01), and TIMP4, ADAMTS5, and ADAMTS15 (all at P < 0.05). Correlation analysis revealed that groups of genes across the gene families were coexpressed in cartilage.Conclusion. This is the first comprehensive expression profile of all known MMP, ADAMTS, and TIMP genes in cartilage. Elucidation of patterns of expression provides a foundation with which to understand mechanisms of gene regulation in OA and potentially to refine the specificity of antiproteolytic therapies.Osteoarthritis (OA) is a debilitating disease that affects ϳ80% of people over the age of 65 (1). Given the current demographic trend toward an older population, OA, for which age is an important risk factor (2), will be an increasing health and economic burden on society.Degradation of articular cartilage is a major feature of OA. Cartilage is made up of 2 main extracellular matrix (ECM) macromolecules, type II collagen and aggrecan, a large aggregating proteoglycan (3,4). The type II collagen scaffold endows the cartilage with its tensile strength, while the aggrecan, by virtue of its high negative charge, swells against the collagen network as it draws water into the tissue, enabling it to resist compression. Quantitatively more minor components (e.g., types IX, XI, and VI collagen, biglycan, decorin, cartilage oligomeric matrix protein, etc.) also have important roles in controlling matrix structure and organization (5).Normal cartilage ECM is in a state of dynamic equilibrium, with a balance between synthesis and degradation. For the degradative process there is a balance between proteinases that degrade the ECM and their inhibitors. It is generally believed that in OA, a disruption of this balance, in favor of proteolysis, leads to pathologic cartilage destruction.The matrix metalloproteinases (MMPs) are a family of 23 enzymes in humans which facilitate ECM turnover and breakdown under normal and disease conditions (6). The MMP family contains the only mammalian proteinases that can specifically degrade triple-helical collagens at neutral pH. These so-called collagenases specifically cleave a single locus in all 3 collagen chains at a point three-quarters from the N-terminus of...

Gastric cancer (GC) is associated with chronic inflammation; however, the molecular mechanisms promoting tumorigenesis remain ill defined. Using a GC mouse model driven by hyperactivation of the signal transducer and activator of transcription (STAT)3 oncogene, we show that STAT3 directly upregulates the epithelial expression of the inflammatory mediator Toll-like receptor (TLR)2 in gastric tumors. Genetic and therapeutic targeting of TLR2 inhibited gastric tumorigenesis, but not inflammation, characterized by reduced proliferation and increased apoptosis of the gastric epithelium. Increased STAT3 pathway activation and TLR2 expression were also associated with poor GC patient survival. Collectively, our data reveal an unexpected role for TLR2 in the oncogenic function of STAT3 that may represent a therapeutic target in GC.

These results suggest that, in human cells, the DNA-damage checkpoint involves direct inactivation of Cdc25 catalyzed by Cds1 and/or Chk1.