TUMOR NECROSIS FACTOR-α (TNF-α)

Figure 6: Different forms of TNF-α.

Two forms of TNF-α present i.e. a) Soluble TNF-α (or secreted form) and b) Membrane TNF-α (or cell associated). Binding of TNF-α to its receptors TNFR1 and TNFR1 triggers intracellular signaling cascade. Upon activation, TNF receptor forms trimer which binds to the monomer of TNF-α which leads to the conformational change in to the structure of receptor.

Reprinted from Palladino et al. 2003: Anti-TNF-α therapies: the next generation: Nature Reviews Drug Discovery 2, 736-746 (September 2003). Copyright (2014), with permission from Nature publishing group.

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TNF-α was first identified as an endotoxin-induced glycoprotein which causes haemorrhagic necrosis of sarcomas in a mouse model. In 1984, the cDNA of TNF-α was first cloned and shown to have the structural and functional homology to lymphotoxin (LT) β and was described as (LT) α^75,76. TNF proteins are ubiquitously expressed by different cell types of the innate and acquired immunity such as B cells, T cells, NK cells, DCs, and monocytes³. TNF-α is expressed in two different forms, one is the cell-associated or membrane TNF-α (26-kDa) and the other one is the secreted or soluble TNF-α (17-kDa) form ⁷⁷(Fig. 6). Both forms of TNF-α are biologically active. The cell-membrane bound form of TNF-α is thought to be responsible for juxtacrine signalling whereas secreted form for the direct cell-to-cell contact, though the exact functions of these two forms are still controversial ^77,78. Based on numerous studies, TNF-α is considered as one of the best known proinflammatory cytokine having a crucial role in host defense and inflammatory diseases^79,80. It has been associated with the development of many autoimmune disorders such as rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease⁷⁷. TNF-α is also known to enhance disease severity by its capability to induce different proinflammatory cytokines, such as IL-1 and different chemokines⁸¹. The administration of TNF-α antibodies and its interference with the TNF pathway are widely used for controlling pathogenesis of many diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease ^77,81. Since the last 10 years, monoclonal antibodies against TNF-α or its receptor are widely used in the clinic for the blockage of TNF pathway⁸¹ for the treatment of autoimmune diseases like rheumatoid arthritis, but also psoriasis.

1.4.2 Role of TNF-α in skin irritation

The exposure of the skin to various irritants or chemicals results in skin irritation. Skin irritation is a complex process which involves a series of responses such as skin damage, cell death and activation of keratinocytes and other cells⁸². Keratinocytes are well known to produce large amounts of proinflammatory cytokines such as TNF-α, IL-1β, IL-6 (Fig. 5)¹⁴. The upregulation of TNF-α in the skin during irritation has been shown by different irritants e.g. dimethyl sulfoxide, PMA, formaldehyde,

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tributyltin, and SLS⁶⁷. TNF-α has pleiotropic effects on keratinocytes and endothelial cells, where it increases the expression of major histocompatibility complex class II molecules and upregulates cell adhesion molecules e.g ICAM-1. TNF-α is also capable of inducing inflammatory factors such as IL-1, IL-6, IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF) and CXC ligand 8 (CXCL8)⁵⁶. During irritation, TNF-α has common functions with IL-1α as a primary alarm signal to other cell types, to further initiate the release of CCL20 and CXCL8 chemokines production from macrophages. An increased expression level of CCL20 and CXCL8 leads to the migration of cells to the site of injury. T-cells, but also immature DCs are activated⁸³. The important role of IL-1α and TNF-α in the pathogenesis of skin irritation has been proven at genetic levels. It has been shown, that certain genetic polymorphisms of both TNF-α and IL-α are linked with an altered risk of skin irritation.

Individuals with TNFA-308 polymorphisms have a lower risk to develop ICD whereas TNFA-238 alleles have an increased risk to ICD. Likewise, IL1A-889 C/T alleles are protective for the development of ICD, clearly indicating that these genetic polymorphisms are associated with an increased or decreased risk of ICD development⁶⁷. Hanel et al 2013 have shown the involvement of TNF-α in barrier repair. TNF-α inhibited the expression of skin barrier genes such as filaggrin and loricrin, TNF-α thereby weakening the skin barrier³. The central role of TNF-α in skin irritation was further confirmed by the direct administration of TNF neutralizing antibodies in vivo. These studies show, that the skin inflammation was reduced upon antibody administration^84,85.

1.4.3 Role of TNF-α in AD

The direct role of TNF-α for the development of AD is not completely understood. A detailed analysis of the literature revealed a negative association between TNF and AD development^86-89. The most remarkable evidence for a functionally relevant inverse association between TNF and AD comes from different clinical studies, which have reported the onset of possible AD as a side effect upon anti-TNF therapy in single patients with rheumatoid arthritis, Crohn's disease and psoriasis ^90,91. On the other hand few reports show a beneficial effect of TNF-α directed therapy in single 26

AD patients⁹². These patients suffered from AD subsets (long-lasting and/or combined with contact dermatitis). Another evidence of defective TNF production in AD patients came from an analysis of peripheral blood leukocytes, in which decreased TNF-α production was consistently reported in AD patients^87-89. Recent studies indicated that cytokines like IL-1β, IL-4, IL-5, IL-12, and IFN-γ are enhanced, whereas TNF-α levels are reduced in AD skin compared to healthy controls⁸⁸. Although TNF-α is undoubtedly one of the best-characterized proinflammatory cytokines, it can also exert anti-inflammatory effects and contribute to the resolution of inflammatory diseases by various mechanisms, e.g. by promoting cluster of differentiation (CD) 4+CD25+ T regulatory cells⁹³, by mediating apoptosis of auto-reactive effector T cells⁹⁴ and by inducing local glucocorticoid production⁹⁵.