Involvement of NF-κB signalling in skin physiology and disease

Abstract

Transcription factors of the nuclear factor-κB (NF-κB)/Rel family play a crucial role in gene regulation during a variety of different cellular processes. This review focuses on the increasing knowledge of the role of NF-κB in skin physiology and pathology. Several studies demonstrate that NF-κB, or components of the system such as IκB kinase (IKK)-α, seem to be involved in epidermal development and differentiation. Furthermore, a dysregulation of NF-κB is suggested to play an important role in skin pathology, including proliferative disorders, e.g. psoriasis, inflammatory processes such as incontinentia pigmenti (IP), sunburn, Lyme disease, allergic contact dermatitis and autoimmune diseases, as well as also in skin carcinogenesis. However, although the knowledge concerning the role of NF-κB in the homeostasis of the skin is steadily increasing, many more questions need to be answered.

Introduction

Nuclear factor-κB (NF-κB)/Rel transcription factors play a central role in the regulation of genes involved in a variety of cellular processes [1], [2], [3]. They are crucial mediators of immune and stress responses, exert pro- and antiapoptotic effects and are important in cell proliferation and differentiation. Dysregulation of the NF-κB system is thought to be involved in acute and chronic inflammatory processes as well as in cancer [4], [5].

The regulatory NF-κB complex consists of two subunits, which can form homo- or heterodimers [1], [3]. The prototypic and best-understood NF-κB complex is composed of p50 and p65 (RelA). Other subunits have been identified, namely p52, c-Rel and RelB, as well as the precursor proteins of p50 and p52, p105 and p100, respectively. In the cytosol of unstimulated cells, the dimeric NF-κB complex is present in an inactive state bound to inhibitory IκB proteins. Several inhibitors have been identified, namely IκB-α, -β and -ε [1], [6], [7]. In addition, the aforementioned precursor proteins p105 (IκB-γ) and p100 (IκB-δ) may also act as inhibitors [8]. Stimulation of cells induces the phosphorylation of the IκB proteins followed by poly-ubiquitination and subsequent proteolysis of these molecules. Phosphorylation of the inhibitory proteins, the initial regulated step of IκB degradation and thus NF-κB activation, is mediated by cytosolic high molecular weight complexes, collectively termed the IκB kinase (IKK) complex [9], [10]. Three subunits of this complex have been identified: two kinase-active proteins, IKK-α (IKK1; 85 kDa) and IKK-β (IKK2; 87 kDa), which are the IκB phosphorylating kinases and are able to form homo- or heterodimers, as well as IKK-γ (NF-κB essential modulator, NEMO; IKK associated protein 1, IKKAP1; 50 and 52 kDa) which is a regulatory adaptor protein [9], [10], [11], [12], [13]. The phosphorylation of IκB occurs at two specific N-terminal serine residues of the IκB proteins: IκB-α at Ser-32/Ser-36, IκB-β at Ser-19/Ser-23 and IκB-ε at Ser-18/Ser-22 [1], [6], [7]. The subsequent ubiquitination takes place on two specific lysine residues, for example on Lys-21/Lys-22 of IκB-α [9], [13]. Finally, the proteolysis is mediated by a multiprotein complex, the 26S proteasome [1], [8]. Few exceptions have been found to this universal pathway for NF-κB activation. One example is the activation of NF-κB in response to ultraviolet radiation, which although dependent on IκB degradation does not involve IκB phosphorylation at the N-terminal sites [14], [15]. The removal of the IκB inhibitor allows the translocation of activated NF-κB into the nucleus, where the transcription factor binds to specific κB promotor and enhancer DNA elements and, together with other transcription factors, regulates the transcription of many different genes [1], [3], [6].

More than 150 different stimuli and conditions are able to modulate the NF-κB system: proinflammatory cytokines (e.g. tumour necrosis factor, TNF; interleukine-1, IL-1), bacteria and bacterial products, viruses, growth factors as well as different forms of stress: physical (ultraviolet radiation), oxidative or environmental [1], [3], [16], [17].

Activation of NF-κB subsequently induces the expression of more than 150 genes: cytokines (TNF, IL-1, IL-6), chemokines (monocyte chemotactic protein-1, MCP-1; IL-8), cell adhesion molecules (intercellular adhesion molecule-1, ICAM-1; vascular cell adhesion molecule-1, VCAM-1), growth factors and proteases [1], [3], [16]. Remarkably, NF-κB induces the production of proteins which are themselves able to stimulate NF-κB, for example TNF and IL-1. IκB-α is itself transcriptionally regulated by NF-κB, allowing for a tight autoregulatory loop.

The skin is subject to a vast array of injuries, infections and inflammations and harbours many immune cells which interact through blood and lymph vessels with other organs. The resulting diseases may affect the whole body. Large amounts of IL-1α/β as well as TNF are produced within the skin (for review see Ref. [18]). After binding to their respective receptors, these cytokines activate several cellular signalling pathways, amongst them the NF-κB system. NF-κB then induces the production of cytokines and chemokines in keratinocytes, fibroblasts, endothelial cells and other skin related cells, which leads to the recruitment of T-cells into the skin. Since the understanding of the role and involvement of NF-κB in many biological mechanisms has steadily increased in recent years, we want to give an overview on the participation of NF-κB in skin biology and diseases.