TUMOR NECROSIS FACTOR ALPHA (TNF-a)

Tumor necrosis factor alpha (TNF, TNFSF2) is an important multifunctional cytokine that regulates inflammation, host defense, immune responses, and apoptosis. TNF exists as a membrane-bound 26kDa, type II integral membrane protein, and a 17kDa soluble homotrimeric TNF that is generated via proteolytic cleavage by TNF-a converting enzyme (TACE, ADAM17). Both the membrane-bound and soluble forms of TNF can interact with either the 55 kDa, type I tumor necrosis factor receptor (TNFRSF1A, TNFR1) or the 75kDa, type II TNF receptor (TNFRSF1B, TNFR2). TNFR2, however, may be preferentially activated by membrane-bound TNF rather than soluble TNF, which may lead to qualitatively distinct TNF responses. The main biologic function of TNF is to induce inflammation via the upregulation of gene transcription, primarily through the NF-kB and AP-1 signaling pathways, which leads to the expression of a large number of genes. TNF plays an important role in innate immunity and host defense against bacterial, fungal, and parasitic pathogens and is particularly important for host defense against intracellular organisms, such as Mycobacterium tuberculosis. TNF has also been implicated in the pathogenesis of pulmonary diseases, such as idiopathic pulmonary fibrosis, emphysema, sarcoidosis, acute lung injury, bacterial pneumonia, and asthma.