TNF-α in asthma
Introduction
Tumour necrosis factor (TNF)-α is an important cytokine in the innate immune response, which provides immediate host defence against invading organisms before activation of the adaptive immune system [1]. It is principally produced by macrophages in response to activation of membrane-bound pattern-recognition molecules, which detect common bacterial cell surface products such as polysaccharide, carbohydrates and lipopolysaccarides. TNF-α is initially produced as a biologically active 26kDa membrane-anchored precursor protein [2], which is subsequently cleaved, principally by TNF-α-converting enzyme [3], to release the 17kDa free protein. These proteins form biologically active homotrimers [4] that act on the ubiquitously expressed TNF-α receptors 1 and 2 (p55 and p75, or TNFR1 and TNFR2) [5]. This receptor–ligand interaction causes intracellular signalling without internalisation of the complex, leading to phosphorylation of nuclear factor-κB and thus activation of the p50-p65 subunit, which then interacts with the DNA chromatin structure to increase transcription of pro-inflammatory genes such as interleukin (IL)-8, IL-6 and TNF-α itself. The response to TNF-α activation is balanced by shedding of the extracellular domain of the TNF-α receptors.
Here, we review the evidence associating TNF-α with asthma airway biology, and summarise the findings of currently published clinical trials of anti-TNF-α therapy in asthma.
Section snippets
Biological activities of TNFα in relation to asthma
Dysregulated TNF-α responses have been implicated in several inflammatory conditions. In rheumatoid arthritis — a common destructive arthropathy in which TNF-α is produced by macrophages and monocytes in response to activation by CD4+ T cells — TNF-α is measurable in increased concentration in the synovial fluid and in the serum [6]. Antagonism of TNF-α in patients with rheumatoid disease, through treatment with either recombinant soluble receptors or neutralising antibodies, leads to
Clinical trials of anti-TNF-α therapy
The current commercially available TNF-α blockers are infliximab (a chimeric mouse/human monoclonal antibody), etanercept (a soluble fusion protein combining two p75 TNF receptors with a Fc fragment of human IgG1) and adalimumab (a fully human monoclonal antibody). Clinical trials of anti-TNFα therapy in asthma are summarised in Table 1.
In an uncontrolled study of etanercept in severe (Global Initiative on Asthma [GINA] stage V) asthma, Howarth et al. [26•] demonstrated a significant (2.5
Conclusions
In summary, TNF-α is a potentially important cytokine in refractory asthma, and preliminary studies on small numbers of patients have demonstrated an improvement in lung function, airway hyperresponsiveness, asthma quality-of-life and exacerbation rate following treatment with anti-TNF therapy. These findings, however, have not been consistently repeatable, and any potential role for TNF-α antagonism in refractory asthma needs to be established in a sufficiently powered large-scale clinical
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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