**2.2 TNF superfamily**

Tumor necrosis factor superfamily (TNFSF) is a group of cytokines composed of 19 ligands and 29 receptors [14]. This family plays a pivotal role in immunity, inflammation and controlling cell cycle, proliferation, differentiation, and apoptosis [15]. TNFSF receptors can be divided into two different groups depending on the presence or absence of the intracellular death domain (DD) [16]. Signaling via the death domain demands the involvement of adapter proteins Fas-associated death domain (FADD) and TNF receptor-associated proteins (TRADD), leading to the activation of caspases that result in apoptotic death of a cell. The second group of TNFSF receptor signals acts only via adapter proteins termed tumor necrosis factor receptor-associated proteins (TRAFs). The DD containing receptors may use the pathway [17]. The functional activity of TNFSF receptors depends on the cellular context and the balance between pro- and antiapoptotic factors inside the cell and in the environment. Mostly, the TNFSF members are revealed on the cells of immune system and play a notable function in maintaining the equilibrium of T-cell–mediated immune responses by arranging direct signals required for the full activation of effector pool and survival of memory T cells. The TNFSF members are necessary in the development of pathogenesis of many T-cell–mediated autoimmune diseases, such as asthma, diabetes, and arthritis [16].

#### *2.2.1 TNF-α*

Tumor necrosis factor (TNF)-α is classified as homotrimeric transmembrane protein with a prominent role in systemic inflammation. Macrophages/monocytes are capable to produce TNF-α in the acute phase of inflammation, and this cytokine drives a wide range of signaling events within cells, leading to necrosis or apoptosis [17]. The TNF superfamily incorporates receptor activator of nuclear factor κB

(RANK), cluster of differentiation (CD)-40, CD27, and FAS receptor. This protein was discovered in the circulation of animals subsequent to the stimulation of their reticuloendothelial system and lipopolysaccharide (LPS) challenge. This protein has been found to provoke a rapid necrotic regression of certain forms of tumors [16].
