Autocrine, paracrine, cell to cell, and reverse signaling pathways for TNF-α. Ligands, such as TNF-α, are expressed as both transmembrane and in soluble forms. The transmembrane form of the ligand appears to mediate therapeutic effects, but soluble ligand is linked to pathologic effects of TNF-α. Ligands, such as TNF-β, lack the transmembrane domain and thus are expressed only as a soluble protein. TNF-α, made by tumor cells, acts primarily through TNFR1 in an autocrine and paracrine manner. There are also examples of reverse signaling through TNF-α when it binds to its receptor.