Tumor necrosis factor ligands (TNF) family named by the first identified members TNFα and TNFβ is consisting of 19 ligands on the basis of sequence, functional, and structural similarities. All TNF ligands cytokines seem to form homotrimeric with exception of heterotrimeric by Lymphotoxin-alpha/beta (LTα/β). Some of the TNF family members and their functions are listed as following:
TNFα which is also named cachectin is a cytokine with variety of functions. It is involved in apoptosis of some tumor cells, induction of cachexia, causing fever, stimulation of interleukin-1 secretion, cell proliferation and cell differentiation.
LTα and LTβ are cytotoxic for a wide range of tumor cells and they induce cell apoptosis both in vitro and in vivo.
CD40L plays a key role in the development and activation of B-cell.
FASL is a protein on cell surface regulating of the immune system and the progression of cancer.
TNFSF9/4-1BBL is a bidirectional signal transducer that acts as a ligand for TNFRSF9/4-1BB and also contributes to T-cell stimulation.
TNFSF4/OX40L is important in the interaction between T cell and antigen-presenting cell (APC) and also mediates adhesion of activated T cells to endothelial cells.
TNFSF10/TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis of transformed cells and tumor cells, but not normal cells.
TNFα is a key protein of the innate immune system. TNFα is secreted by the host in response to infection by a microorganism, which leads to the inactivation and neutralization of the threat. This innate immune response, of course without the refined features of memory, like the T and B cells, has been around for so long as a first line of protection. Microorganisms have generically evolved in diffuse ways to thwart the TNFα response. Mechanisms to lower biologic TNFα include host shedding of TNFR1 and TNFR2 receptors from cell membranes and many more.
TNFα, aside from being necessary for infection control, also plays an important role for several beneficial immune effects. Tregs require the prescience of TNFα to survive, but exposure of autoreactive T cells in the periphery to this same TNFα causes programed cell death. It has been hypothesized by many that the reason autoimmune diseases and allergies are on the rise, is because there has been the elimination of many infectious diseases. This hypothesis, as stated earlier, is called the Hygiene Hypothesis. We have proposed that TNFα is the central cytokine that is deficient in autoimmune prone households of our clean environment, and deficiencies in this cytokine drive the rising rates of self-reactive diseases.
This hypothesis might seem contradictory since very impressive biologics of anti-TNFα are mainstream therapy for some forms of autoimmunity like rheumatoid arthritis. However, the human data is an important example in that diffuse autoimmune diseases as it relates to possible deficiencies of TNFα causes diverse autoimmune diseases such as type 1 diabetes, multiple sclerosis, celiac disease, and Crohn’s disease.
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