Tumor necrosis factors

Tumor necrosis factors (or the TNF-family) refers to a group of cytokines family that can cause cell death (apoptosis). The first two members of the family to be identified were:
 * Tumor necrosis factor-alpha (TNF-α) is the best-known member of this class, and sometimes referred to when the term "tumor necrosis factor" is used. TNF-α is a monocyte-derived cytotoxin that has been implicated in tumour regression, septic shock and cachexia.  The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine. A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers. Both the mature protein and a partially-processed form of the hormone can be secreted after cleavage of the propeptide.
 * Tumor necrosis factor-beta (TNF-β), also known as lymphotoxin is a cytokine that is inhibited by interleukin 10

Family members
Nineteen cytokines have been identified as part of the TNF family on the basis of sequence, functional, and structural similarities. They include:


 * Tumor Necrosis Factor (TNF) (also known as cachectin or TNF-alpha) is a cytokine that has a wide variety of functions. It can cause cytolysis of certain tumor cell lines; it is involved in the induction of cachexia; it is a potent pyrogen, causing fever by direct action or by stimulation of interleukin-1 secretion; it can stimulate cell proliferation and induce cell differentiation under certain conditions.
 * Lymphotoxin-alpha (LT-alpha) and lymphotoxin-beta (LT-beta), two related cytokines produced by lymphocytes that are cytotoxic for a wide range of tumor cells in vitro and in vivo.
 * T cell antigen gp39 (CD40L), a cytokine that seems to be important in B-cell development and activation.
 * CD27L, a cytokine that plays a role in T-cell activation. It induces the proliferation of costimulated T cells and enhances the generation of cytolytic T cells.
 * CD30L, a cytokine that induces proliferation of T cells.
 * FASL, a cytokine involved in cell death.
 * 4-1BBL, a inducible T cell surface molecule that contributes to T-cell stimulation.
 * OX40L, a cytokine that co-stimulates T cell proliferation and cytokine production.
 * TNF-related apoptosis inducing ligand (TRAIL), a cytokine that induces apoptosis.

All these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognized by their specific receptors. Strong hydrogen bonds between the monomers stabilizes the tertiary structure. One such example is the Asn34-Arg82 hydrogen bond in the M. musculus TNF alpha. The PROSITE pattern for this family is located in a beta-strand in the central section of the protein that is conserved across all members.

All members of the TNF family, with the exception of the secreted lymphotoxin and a proliferation-inducing ligand (APRIL), are type II transmembrane proteins which protrude from immune cells. Such membrane-bound TNF ligands frequently signal back to the immune cells when they contact and bind their cognate receptors on other cells.

Examples
Human proteins containing this domain include:
 * CD40LG;   CD70;      EDA;       FASLG;     LTA;       LTB;
 * TNFSF4;   TNFSF5;    TNFSF7;    TNFSF8;    TNFSF9;   TNFSF10;   TNFSF11;   TNFSF12;   TNFSF13;   TNFSF13B;   TNFSF14;   TNFSF15;   TNFSF18;
 * TWEAK;