Tumour necrosis factor α as a therapeutic target for immune-mediated inflammatory diseases

The Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, 1 Aspenlea Road, London W68LH, UK.
Current Opinion in Biotechnology (Impact Factor: 8.04). 01/2005; 15(6):557-63. DOI: 10.1016/j.copbio.2004.09.005
Source: PubMed

ABSTRACT Preclinical studies have identified and validated tumour necrosis factor alpha (TNFalpha) as a key disease molecule and therapeutic target for immunotherapeutic intervention in many immune-mediated inflammatory diseases. Clinical indications include rheumatoid arthritis, Crohn's disease, ankylosing spondylitis and psoriasis. Recent clinical findings indicate that many chronic inflammatory disorders share certain pathogenic pathways, whereas others are limited to particular disease phenotypes. Better understanding of these pathogenic pathways will inform the development of new therapeutic approaches leading to more complete and sustained disease remissions.

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    • "As DC migration is essential during both steady-state conditions in the absence of inflammation, as well as during inflammation, DCs were co-cultured either with resting fibroblasts or with fibroblasts stimulated with TNFa and IL-1b to mimic a proinflammatory tissue microenvironment. TNFa and IL-1b were chosen as stimuli, as they are highly expressed during cutaneous inflammation (Taylor et al., 2004; Aggarwal et al., 2006). Resting fibroblasts did not significantly enhance the secretion of MMP-9 from immature DCs. "
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    ABSTRACT: Migration of dendritic cells (DCs) from skin to lymph nodes on activation is an essential step in the initiation of an adequate immune response. The dermal microenvironment including stromal cells and their soluble factors might be involved in the regulation of DC migration. To focus on the role of dermal fibroblasts, we studied whether interaction of DCs with fibroblasts promotes the migration of DCs. DCs were co-cultured with resting fibroblasts or with tumor necrosis factor (TNF)alpha/IL-1beta-activated fibroblasts to mimic an inflammatory microenvironment. Interaction of DCs with TNFalpha/IL-1beta-stimulated fibroblasts increased the secretion of matrix metalloproteinase-9 (MMP-9) from DCs within 6 hours compared with DCs alone or DCs stimulated with lipopolysaccharide or TNFalpha/IL-1beta. In contrast, unstimulated fibroblasts did not affect MMP-9 secretion. IL-6 released by TNFalpha/IL-1beta-stimulated fibroblasts was identified as a factor responsible for fibroblast-stimulated MMP-9 secretion from DCs. In accordance with the elevated MMP-9 release, on co-culture with TNFalpha/IL-1beta-stimulated fibroblasts, DCs migrated significantly more effectively through matrigel matrices than did TNFalpha/IL-1beta-stimulated DCs. This was inhibited by a selective blocking of MMP-9, indicating the importance of MMP-9 for this migratory capacity of DCs. In summary, fibroblasts in the local dermal microenvironment are capable of potentiating the migratory capacity of DCs, and thus have the potential to actively participate in the regulation of a cutaneous immune response.
    Journal of Investigative Dermatology 09/2009; 130(2):444-54. DOI:10.1038/jid.2009.253 · 6.37 Impact Factor
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    • "TNFa was identified as a key pathogenic molecule in rheumatoid arthritis as well as in Crohn's disease, ankylosing spondylitis and psoriasis. Recent clinical research using biological therapies for targeting TNFa demonstrates the important common role of TNFa in molecular pathways across a range of chronic immunomediated disease phenotypes [34]. Other major cytokines identified at inflammatory cites include IL-6, IL-1h, interferon-g and transforming growth factor h [35]. "
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    ABSTRACT: Various nutrients and plant-derived phytochemicals are associated with a reduced risk of many diet-related chronic diseases including cardiovascular disease, cancer, diabetes, arthritis and osteoporosis. A common theme that links many chronic diseases is uncontrolled inflammation. The long-chain (LC) omega-3 polyunsaturated fatty acids (PUFA) and flavonoids are known to possess anti-inflammatory actions in cell cultures, animal models and humans. Minimizing the condition of persistent inflammation has been a primary aim for drug development, but understanding how food components attenuate this process is at the nexus for improving the human condition. The prevalence of environmental toxins such as heavy metals and organics that contribute to diminished levels of antioxidants likely aggravates inflammatory states when intakes of omega-3 PUFA and flavonoids are marginal. Scientists at Purdue University have formed a collaboration to better understand the metabolism and physiology of flavonoids. This new effort is focused on determining how candidate flavonoids and their metabolites affect gene targets of inflammation in cell culture and animal models. The challenge of this research is to understand how LC omega-3 PUFA and flavonoids affect the biology of inflammation. The goal is to determine how nutrients and phytochemicals attenuate chronic inflammation associated with a number of diet-related diseases that occur throughout the life cycle. The experimental approach involves molecular, biochemical and physiological endpoints of aging, cancer, obesity and musculoskeletal diseases. Examples include investigations on the combined effects of PUFA and cyanidins on inflammatory markers in cultures of human cancer cells. The actions of catechins and PUFA on muscle loss and osteopenia are being studied in a rodent model of disuse atrophy to explain how muscle and bone communicate to prevent tissue loss associated with injury, disease and aging. The purpose of this review is to introduce the concept for studying food components that influence inflammation and how LC omega-3 PUFA and flavonoids could be used therapeutically against inflammation that is mediated by environmental pollutants.
    The Journal of Nutritional Biochemistry 04/2007; 18(3):196-205. DOI:10.1016/j.jnutbio.2006.12.002 · 4.59 Impact Factor
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    ABSTRACT: To study the effects of propyl gallate on the interaction of tumor necrosis factor-alpha (TNF-alpha) with its soluble receptor, sTNFR-I. Interactions between TNF-alpha and sTNFR-I were analyzed using an IAsys biosensor. sTNFR-I was immobilized on the carboxymethyl dextran (CMD) surface of the IAsys biosensor cuvettes, and TNF-alpha preincubated with different concentrations of propyl gallate was added to the cuvettes. The resonant angle shift caused by the binding between TNF-alpha and sTNFR-I was then recorded. sTNFR-I was immobilized on the CMD surface at a density of 2.76 ng/mm(2). TNF-alpha then bound the immobilized sTNFR-I specifically, and propyl gallate was able to enhance the binding between TNF-alpha and sTNFR-I in a dose-dependent manner. The binding between TNF-alpha and sTNFR-I is one of the targets that propyl gallate can act on in vivo. The IAsys biosensor offers a new clue as to the study on the mechanisms of action of propyl gallate.
    Acta Pharmacologica Sinica 11/2005; 26(10):1212-6. DOI:10.1111/j.1745-7254.2005.00198.x · 2.50 Impact Factor
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