TNF Family Ligands

See also signal transduction

What they do

TNF and its family members represent a double edged sword. Whereas physiologically they are important cytokines and required for normal responses, their inappropriate expression is harmful.  Among the functions of TNF superfamily members are the following:

anticancer potential: Although initially thought to be a potent anticancer agent, it is now believed that TNF has limited acitvity in the supression of cancer, mainly because of its systemic toxicity. If this systemic toxicity could be suppressed, the therapeutic usefulness of tNF might increase.

Certain cytokines of the TNF ligand family and their cognate receptors, including TNFR-1 and Fas are classic triggers of the suicide response. TNF and Fas ligand induce apoptosis by binding to their respective death domain-containing receptors, TNFR-1 and Fas. The death domain is a protein-protein interaction motif that orchestrates the assembly of a signaling complex leading to the recruitment of pro-apoptotic proteases (caspases).

On the dark side, TNF has also been shown to be an autocrine growth factor for a wide variety of tumours. Through the activation of NF-kB, TNF induces the expression of various genes that are involved in invasion and metastasis, including adhesion molecules, urokinase plasminogen actiation (UPA), matrix metalloproteinase 9 (MMP9), cyclo-oxygenase 2 (COX2) and vascular endothelial growth factor (VEGF). In addition, activation of NF-kB can suppress apoptosis, which further contributes to tumorigenesis.

regulation of the immune system:The immune system is regulated not only by cell proliferation and differentiation, but also by apoptosis.

protection against microbial infection: An effective host response against infection with bacteria depends partly on the ability to produce an appropriate Th1 type cytokine profile, but TNFR signalling is also involved. It has been shown that deletion of either TNF or TNFR1 in mice leads to increased susceptibility to certain types of bacterial.

Autoimmunity: several TNF ligands have been implicated in the development of autoimmunity. For example, transgenic overexpression of BAFF results in many autoimmune symptoms in mice. It is also becoming apparent that TNF has an important role in the pathogenesis of type II diabetes mellitus. TNF has been shown to interfere with an insulin-signalling mechanisms by inhibiting the tyrosine kinase activities of the insulin receptor and serine phosphorylation of the insulin receptor substrate 1.

Other diseases: Ligands of the TNF superfamily have also been linked with chronic heart failure, bone resorption, AIDS, Alzhemier's disease, transplant rejection, atherosclerosis and hepatotoxicity.

Members of the TNF Superfamily

At present 19 different ligands have been identified that belong to the TNF superfamily.  Some examples include:

• TRAIL/Apo2L (TNF-related apoptosis inducing ligand), also known as "Apo-2 Lgand is another member of the TNF ligand family which also induces rapid apoptosis in transformed cell lines of diverse origin. The ability of TRAIL to kill transformed cells, as well as the resistance of normal cells to TRAIL, has led to its preclinical evaluation as a potential therapy for selected human malignancies. TRAIL induces target cell apoptosis via TRAIL-R1 and TRAIL-R2, which recruit FADD or a FADD-like adaptor and activate FLICE or FLICE-2 (caspase-10) and the subsequent caspase cascade. However, it has been shown that TRAIL-R1 and TRAIL-R2 also recruit tRADD and activate NF-kB, which may act protectively against apoptosis. Moreover, Trail also binds to antagonistic receptors, including TRAIL-R3 which lacks a cytoplasmic domain, and TRAIL-R4, which does not induce apoptosis but activates NF-kB and protects against TRAIL-R1 and TRAIL-R2 mediated apoptosis.

TRAIL has received great attention because of its potential therapeutic applications. Indeed, it has been reported that TRAIL specifically induces apoptosis in virus infected and tumor cells. TRAIL has also been described as a potent inhibitor of autoimmune arthritis and inflammation. Indeed, TRAIL inhibits activated T cell proliferation and cytokine production. This suggests that TRAIL may not only be an innate immunity effector molecule involved in the elimination of virus infected or tumoral cells, but also it may play an inhibitory role in adaptive immunity through limiting T cell activation.

• FasL is synthesized as a type II-membrane protein in that its N terminus is in the cytoplasm and its C-terminal region extends into the extracellular space. Membrane bound FasL undergoes metalloproteinase-mediated proteoytic cleavage to generate soluble cytokine. Fas induces target cell apoptosis via its receptor, Fas, which recruits FADD and activates FLICE (FADD-like IL-1B-converting enzyme; caspase 8) and the subsequent caspase cascade. Note however, that Fas expression alone does not always determine the suspectibility to FasL-induced apoptosis, which may be explained by the expression of antiapoptotic molecules such as Bcl-2 or FLIP, which antagonizes FLICE.

The expression of FasL by testicular Sertoli cells and by parenchymal cells of the anterior chamber of the eye enables them to kill any activated, Fas-expressing T cells and makes these tissues immune privileged sites.

• TRANCE is a TNF family member expressed on T cells that promotes dendritic cell survival but not maturation.
• TWEAK is a recently identified member of the TNF family that exhibited cytotoxic activity against some tumor cell lines in vitro. It has also been reported that TWEAK activated nuclear factor (NF)-kB in some tumor cells and induced proliferation of endothelial cells and angiogenesis.

lymphotoxin

CD30L

4-1BBL

CD40 ligand

CD27L

RANKL is a member of the TNF ligand family that plays a role in osteoclase differentiation, activation of mature osteoclasts, and interactions between T cells and dendritic cells. RANKL binds to 2 receptors, RANK and osteoprotegerin (OPG).

EDA:

APRIL:

TNF superfamily signal transduction

The 19 ligands of the TNF family mediate their cellular respond through 29 receptors that belong to the TNF receptor (TNFR) superfamily. After binding to their receptor, members of the TNF superfamily either mediate apoptosis ( such as TNF, LT, CD95L, TRAIL, VEGI, TWEAK and LIGHT (e.g., LIGHT-HVEM induces IFNy. LIGHTTg induces T cell expansion and inflammation. LIGHT is reduncant with LTbeta in mesenteric LN formation. LIGHT mediates tumor rejection. LIGHT), survival (such as RANKL and BAFF), differentiation (such as TNF, RANKL and DR6) or proliferation (such as TNF, CD27L, CD30L, CD40L, OX40L, 4-1BBL, APRIL and BAFF) throught he activation of pathways involving NF-kB, JUN N-terminal kinase (JNK), p42/p44 mitogen activated protein kinase (MAPK) and p38 MAPK. Signalling through TNF and CD95 has been a paradigm for most other members of the TNF superfamily.

 Targeting the TNF Superfamily

One strategy is to use neutralizing antibodies. For example, EgG used to target TRAILR in cancer. IgG to tartet LTbetaR in cancer/infectious disease.

Another strategy is to use the Fc receptor in combination with a TNF receptor as inhibitor of TNF lgiands. For example, TNFR2-Rc as an inhibitor against TNF for reheumatoid arthritis.

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