Anti-TNF therapy for rheumatoid arthritis and other inflammatory diseases.
ABSTRACT The availability of agents that block the biological activity of tumor necrosis factor alpha (TNF alpha) in rheumatoid arthritis (RA) has permitted studies that confirm the key role of this cytokine in the pathogenesis of this disease. To date, two anti-TNF agents, infliximab and etanercept, have been approved for use in treatment. Clinical trials of these agents demonstrate efficacy for the control of symptoms and signs and acceptable safety in patients who have failed to respond adequately to conventional therapy. Combination with methotrexate appears to be particularly effective and may provide the main initial indication for clinical application in the first instance. Repeated administration of anti-TNF therapies over a one year period results in sustained reduction in symptoms and signs of RA in the majority of patients. It has recently become apparent that anti-TNF therapy protects joints from structural damage. These findings imply that TNF alpha has a critical role in the bone and cartilage damage associated with RA. Evidence to date support the hypothesis that there are 2 particularly important mechanisms of action; deactivation of the proinflammatory cytokine cascade at the site of inflammation and diminished recruitment of inflammatory cells from blood to the rheumatoid joint.
Article: The transcription factor ST18 regulates proapoptotic and proinflammatory gene expression in fibroblasts.[show abstract] [hide abstract]
ABSTRACT: Suppression of tumorigenicity 18 (ST18) and the homologues neural zinc-finger protein-3 (NZF3) and myelin transcription factor 3 (Myt3) are transcription factors with unknown function. Previous studies have established that they repress transcription of a synthetic reporter construct consisting of the consensus sequence AAAGTTT linked to the thymidine kinase promoter. In addition, ST18 exhibits significantly reduced expression in breast cancer and breast cancer cell lines. We report here for the first time evidence that ST18 mediates tumor necrosis factor (TNF) -alpha induced mRNA levels of proapoptotic and proinflammatory genes in fibroblasts by mRNA profiling and silencing with ST18 small interfering RNA (siRNA). Gene set enrichment analysis and mRNA profiling support this conclusion by identifying several apoptotic and inflammatory pathways that are down-regulated by ST18 siRNA. In addition, ST18 siRNA reduces TNF-induced fibroblast apoptosis and caspase-3/7 activity. Fibroblasts that overexpress ST18 by transient transfection exhibit significantly increased apoptosis and increased expression of TNF-alpha, interleukin (IL) -1alpha, and IL-6. In addition, cotransfection of ST18 and a TNF-alpha or IL-1alpha reporter construct demonstrates that ST18 overexpression in fibroblasts significantly enhanced promoter activity of these genes. Taken together, these studies demonstrate that the transcription factor ST18/NZF3 regulates the mRNA levels of proapoptotic and proinflammatory genes in revealing a previously unrecognized function.The FASEB Journal 09/2008; 22(11):3956-67. · 5.71 Impact Factor
Article: Biological targets in the treatment of rheumatoid arthritis: a comprehensive review of current and in-development biological disease modifying anti-rheumatic drugs.[show abstract] [hide abstract]
ABSTRACT: Enhanced understanding of the rheumatoid arthritis (RA) pathophysiology and the role of cytokines has enabled the development of innovative biological agents in the last 10 years that target specific parts of the immune response. Failure to achieve adequate response with traditional disease modifying anti-rheumatic drugs (DMARDs) and increasing evidence of ongoing radiographic deterioration of the affected joints despite seemingly clinical response were essential stimuli for the development of biologics. The current and upcoming biological agents are primarily aimed at neutralizing circulating and cell-bound pro-inflammatory cytokines, interfering in the interaction of antigen-presenting and T-lymphocytes, eliminating circulating B-lymphocytes or by interfering with the intracellular signaling mechanisms of immuno-competent cells that lead to inflammation. These agents have improved the currently available treatments due to greater efficacy, fast action and greater tolerability. However, use of these agents has also been associated with significant, although rare, adverse events and considerable cost. Therefore, these agents should be used with caution by experienced clinicians. The present work aims to provide a global and updated review of the current and in-development biological DMARDs for the treatment of RA.Biologics: Targets & Therapy 01/2009; 3:443-57.
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ABSTRACT: Cyclin-dependent kinases (CDKs) and their targets have been primarily associated with regulation of cell-cycle progression. Here we identify c-Jun, a transcription factor involved in the regulation of a broad spectrum of cellular functions, as a newly recognized CDK substrate. Using immune cells from mouse and human, and several complementary in vitro and in vivo approaches including dominant negative protein expression, pharmacologic inhibitors, kinase assays and CDK4 deficient cells, we demonstrate the ability of CDK4 to phosphorylate c-Jun. Additionally, the activity of AP-1, a ubiquitous transcription factor containing phosphorylated c-Jun as a subunit, was inhibited by abrogating CDK4. Surprisingly, the regulation of c-Jun phosphorylation by CDK4 occurred in non-dividing cells, indicating that this pathway is utilized for cell functions that are independent of proliferation. Our studies identify a new substrate for CDK4 and suggest a mechanism by which CDKs can regulate multiple cellular activation functions, not all of which are directly associated with cell cycle progression. These findings point to additional roles of CDKs in cell signaling and reveal potential implications for therapeutic manipulations of this kinase pathway.PLoS ONE 01/2011; 6(4):e19468. · 4.09 Impact Factor