Genomic structure, induction, and production of TNF-alpha

The TNF gene is located in close proximity to the HLA-B locus in both humans and mouse. TNF has a high degree of sequence observation across species, and this is reflected in its relatively high cross-species activity. The 5' flanking region of the TNF gene contains multiple potential regulatory sites, including consensus sequences for the AP-1 and AP-2 sites, the cAMP-responsive element, and sequences similar to the kappa B sequences found in immunoglobulin and cytokine regulatory elements. This sequence has been demonstrated to be responsive to LPS and TNF stimulation. The 3' untranslated region contains a sequence element affecting posttranslational control of TNF through mRNA stability and translation efficiency. The functional importance and interactions of these regulatory elements remain undefined. TNF is widely expressed in granulocytes, macrophages, fibroblasts, and epithelial cells. Induction of TNF can occur through a variety of stimuli, including LPS, TPA, cytokines, calcium flux, and oxygen free-radical mechanisms. A common pathway for these diverse agents remains unknown. In human monocytes, the regulation of TNF expression is regulated at both transcriptional and posttranscriptional levels. Experimental evidence suggests that phospholipase A2 and the lipoxygenase pathway may be central in the process of TNF induction in leukocytes. Down-regulation of TNF expression is better understood. The inhibition of expression appears to result from high levels of cAMP, frequently induced through the action of PGE2. TNF secretion is separately regulated and may involve the action of G binding proteins.