Tumor Necrosis Factor - Family Members

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 co-stimulated 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 stabilize 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.

Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities. Tumor necrosis factor (TNF) (also known as TNF alpha or cachectin) 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 are secreted after cleavage of the propeptide.