Emerging role of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) as a key regulator of inflammatory responses.

1. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumour cells while leaving most non-transformed cells unharmed. Binding of TRAIL to its death receptors (DR4 and DR5) activates the extrinsic apoptotic pathway by recruiting procaspase 8 into the death-inducing silencing complex. Cleavage of the BH-3 only peptide Bid by caspase 8 links the apoptotic TRAIL signal to the mitochondrial pathway and the subsequent release of cytochrome c. 2. In addition, TRAIL binds to neutralizing decoy receptors (DcR1 and DcR2). Signalling through DcR2, DR4 and DR5 can activate pro-inflammatory intracellular molecules such as mitogen-activated protein kinase, protein kinase B and nuclear factor-kappaB. 3. Recent studies have identified an important role for TRAIL in regulating immune responses to viruses, self-antigen and allergens. Increased concentrations of TRAIL are found in virus infections of the lung and TRAIL affects the antiviral response and resolution of infection. In addition, TRAIL is upregulated in the airways of asthmatics and inhibition results in reduced inflammation, T helper 2 cytokine and CCL20 release, as well as abolishing the development of airway hyperreactivity in experimental models. 4. Characterization of the specific receptor systems activated and the pro-inflammatory factors regulated by TRAIL in vivo may lead to the development of novel therapeutic strategies for diseases as diverse as infection, autoimmunity and asthma.