TWEAK/Fn14 activation induces keratinocyte proliferation under psoriatic inflammation

Abstract

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) has been reported to induce keratinocyte apoptosis in vitro by engaging its sole receptor of fibroblast growth factor-inducible 14 (Fn14). In this study, we explored the role of TWEAK/Fn14 pathway in the growth of psoriatic keratinocytes that is, however, characterized by suppressed apoptotic cell death. Skin tissues from the patients with psoriasis or healthy donors were determined for TWEAK and Fn14 expression, and primary keratinocytes were evaluated under the stimulation of psoriatic proinflammatory cytokines or plus TWEAK. The results showed that both TWEAK and Fn14 were highly expressed in psoriatic skins. Moreover, the stimulation of psoriatic cytokines enhanced Fn14 expression by keratinocytes in vitro, which expressed TNF receptor 2 predominantly and proliferated increasingly with the addition of TWEAK. Furthermore, TWEAK stimulation enhanced the synthesis of survivin, inhibitor of apoptosis protein 2 and cellular FLICE-inhibitory protein in lesional keratinocytes. Therefore, TWEAK/Fn14 interaction prefers to enhance proliferation but not apoptosis of keratinocytes under psoriatic inflammation. The activation of nuclear factor-κB signalling-dependent anti-apoptotic proteins and biased expression of TNF receptors may be responsible for such a novel principle in keratinocytes under psoriatic inflammation.

Tumor Necrosis Factor Receptor Mediates Fibroblast Growth Factor-Inducible 14 Signaling

“…TWEAK not only induces cell growth, which contributes to tissue repair after acute injuries, but also plays a critical role in pathologic hyperplasia involving arthritis (pannus formation), colitis (crypt epithelization), neurodegenerative diseases (glial hyperplasia), and cancers [14]. TWEAK/Fn14 interaction activates classic nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signals, which are suggested to enhance RANTES expression and macrophage infiltration [7]. NF-κB signals are pivotal in the differentiation, proliferation, and survival of cells, as well as the development of tumors, with the latter also associated with inflammation [29].…”

“…Fn14, a type I transmembrane protein [5], has been reported to be expressed in the nervous system, such as in microglia and astrocytes, and in immune cells, including natural killer cells, macrophages, dendritic cells, and Th17 cells [6]. Besides, Fn14 can be expressed in normal keratinocytes, immortal HaCaT cells, or keratinocytes under different inflammatory conditions [7-13]. In healthy tissues, the expression levels of TWEAK and Fn14 are relatively low [6]; however, their expression increases when the tissues are damaged or under inflammation [14].…”

“…Moreover, the TWEAK/Fn14 signals participate in the development of various dermatoses, such as psoriasis [7], atopic dermatitis [8], cutaneous vasculitis [18], human papillomavirus (HPV) infection [9], and bullous pemphigoid [10]. TWEAK/Fn14 activation also contributes to the biological processes of tumors [19].…”

“…Moreover, the same types of cells show diverse cell cycles under various microenvironments. Further, TWEAK/Fn14 signals are involved in cutaneous inflammation and diversely regulate the cell fates of keratinocytes [7-11]. In fact, the regulation of cell fates is central to the function of TWEAK/Fn14 signaling.…”

Selected aspects of apoptosis in psoriasis

“…Badania ostatnich lat wskazują, że pod wpływem stymulacji TWEAK dochodzi do zwiększenia syntezy surwiwiny (inhibitora apoptozy) przez keratynocyty łuszczycowe. Badania te wskazują raczej, że interakcja TWEAK/ Fn14 pobudza proliferację, a nie apoptozę keratynocytów w zmianach łuszczycowych [36]. Doniesienia dotyczące stężenia TWEAK w surowicy są również sprzeczne.…”