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Role of Transcription Factors in Inflammatory Lung Diseases

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Role of Transcription Factors in Inflammatory Lung Diseases Thorax 1998;53:601–612 601 Role of transcription factors in inflammatory lung diseases Thorax: first published as 10.1136/thx.53.7.601 on 1 July 1998. Downloaded from Irfan Rahman, William MacNee Acute and chronic alveolar and/or bronchial nuclear receptor co-activators which facilitate inflammation is thought to be central to the DNA binding of transcription factors,8 notably pathogenesis of many lung disorders such as the CREB-binding protein (CBP), adenovirus asthma, chronic obstructive pulmonary disease E1A-associated protein p300/CBP-associated (COPD), adult respiratory distress syndrome factor (p/CAF), and the steroid receptor (ARDS), and idiopathic pulmonary fibrosis co-activator-1 (SRC-1), which interact with (IPF). The site and specific characteristics of basal transcription factors and transcription the inflammatory responses may be diVerent in machinery and are of particular importance in each of these diseases, but all are characterised the transactivation and regulation of gene tran- by the recruitment to the lungs and activation scription involved in the immune and inflam- of immune and inflammatory cells. These acti- matory responses. Understanding the function vated cells produce cytokines, oxidants and and regulation of basal transcription factors is many other mediators which are involved in fundamental to the study of lung inflammation inflammation.12 Recent data indicate that, in and may provide novel therapeutic strategies addition, airway epithelial cells are able to act for a number of inflammatory lung diseases. In as immune eVector cells by secreting pro- this review we will focus on recent progress in inflammatory mediators, oxidants, and our understanding of the role of the NF-êB, cytokines.3 Once triggered, an inappropriate AP-1, NF-IL6, and NFAT transcription fac- chronic inflammatory response persists in tors in the pathogenesis of inflammatory lung these conditions and is presumed to result in diseases and discuss synergistic interactions lung injury. The intracellular molecular between GR proteins, other families of tran- mechanisms in response to environmental sig- scription factors, and nuclear receptor co- nals, leading to increased gene expression and activators which lead to specific gene regula- biosynthesis of proinflammatory mediators by tion. We will also review the current concepts of pharmacological intervention to modulate airspace inflammatory and epithelial cells, are the activation of these transcription factors. of considerable current interest. It is now recognised that there are gene specific factors http://thorax.bmj.com/ which regulate the transcription of particular NF-êB genes by aYnity binding to specific recognition REGULATION OF NF-êB motifs, which are usually located in the NF-êB was first identified as a nuclear factor upstream (5') promoter region of the gene. that binds the decameric DNA sequence These factors, which are usually located in the 5'-GGGACTTTCC-3' within the intronic cytosol, can translocate to the cell nucleus and, immunoglobulin kappa light chain enhancer in by binding to specific consensus sites, can mature B cells.9 Binding of NF-êB to this DNA upregulate the rate of transcription of the gene sequence is responsible for the inducible activ- on September 30, 2021 by guest. Protected copyright. and therefore increase the formation of mes- ity of the enhancer element present in the senger RNA (mRNA) and the protein of an immunoglobulin gene. NF-êB is a member of inflammatory mediator. Some transcription the Rel family of proteins, a novel family of factors are cell specific, but others are ubiqui- ubiquitous transcription factors sharing a tous. Their activity can be modulated by envi- common structural motif for DNA binding and ronmental signals and they may play a key role dimerisation.10 The Rel family of transcription in immune and inflammatory responses. The factors can be defined as a group of proteins transcription factors about which there is most that share sequence homology over a 300 information in immune and inflammatory amino acid region termed the NF-êB/Rel responses are nuclear factor-kappa (ê)B (NF- domain. These proteins can exist either as êB) and activator protein 1 (AP-1).4 Other homodimers or heterodimers, each with a spe- transcription factors include the nuclear factor cific aYnity for diVerent decamer binding sites for the IL-1 responsive element in the IL-6 fitting the êB motif.10 Several diVerent NF-êB gene (NF-IL6), nuclear factor of activated T proteins have been characterised.10 The classi- cells (NFAT), glucocorticoid receptors (GR), cal activated form of NF-êB is a heterodimer Unit of Respiratory cyclic AMP response element binding proteins which usually consists of two proteins, a 65 kD Medicine, Department (CREB), guanine-adenine and thymine- polypeptide (p65) subunit (also referred to as of Medicine, University of adenine repeats (GATA), E26 transformation Rel A) and a 50 kD polypeptide (p50) subunit. Edinburgh, Royal specific (ets), and the signal transducers and Other subunits, such as p105, a p50 precursor Infirmary, Edinburgh activators of transcription (STAT) families of (NF-êB1), p100, a precursor of p52 (NF- EH3 9YW, UK transcription factors. The binding sites for êB2), c-Rel and Rel B are present in diVerent I Rahman these transcription factors are located in the forms of NF-êB. These subunits form various W MacNee promoter regions of a large variety of genes homodimers and heterodimers which are likely Correspondence to: which are considered to be involved in lung to have diVerent aYnities for DNA and diVer- Professor W MacNee. inflammation.5–7 In addition, there are several ent transactivation potentials of the complexes 602 Rahman, MacNee Table 1 Activators of NF-êB Cytokines Thorax: first published as 10.1136/thx.53.7.601 on 1 July 1998. Downloaded from Tumour necrosis factor á and tumour necrosis factor â Interleukin-1â Interleukin-2 Interleukin-6 Interleukin-8 Protein kinase C activators Phorbol esters Platelet activating factor Oxidants Hydrogen peroxide Ozone Hyperoxia Growth factors GM-CSC G-CSF M-CSF Bacteria and viruses Mycobacteria tuberculi Rhinovirus Influenzavirus Adenovirus Allergens Der p 1 Immunoreceptors T cell receptor MHC class I and II IL-2 receptor Others Lipopolysaccharide Ultraviolet radiation Hypoxia Leukotriene B4 f-Met-Leu-Phe (f-MLP) ACTIVATORS OF NF-êB NF-êB activation represents the terminal step Figure 1 Model for the mechanism of NF-êB and AP-1 activation. Activation of NF-êB in a signal transduction pathway leading from involves the phosphorylation, ubiquitination, and subsequent proteolytic degradation of the the cell surface to the nucleus. A wide variety of inhibitory protein IêB. Free NF-êB then translocates into the nucleus and binds with its extracellular stimuli trigger the activation of êB consensus sites. Antioxidants such as intracellular glutathione and thioredoxin can NF-êB (table 1) including pro-inflammatory inhibit NF-êB activation. Similarly, AP-1 either c-jun/c-jun (homodimer) or c-fos/c-jun 5 10 (heterodimer) migrates into the nucleus and binds with its TRE consensus regions. cytokines, activators of PKC, allergens such 14 Activation of NF-êB/AP-1 leads to gene expression of inflammatory proteins. as Der p 1, and bacterial and viral http://thorax.bmj.com/ 15–17 required to activate diVerent sets of specific products. It may be through NF-êB activa- tion that rhinovirus and influenza virus can genes. In unstimulated cells NF-êB is found in trigger acute exacerbations of asthma. Experi- the cytoplasm as an inactive non-DNA binding mental infection with rhinovirus activates form, associated with an inhibitor protein NF-êB and stimulates the secretion of inter- called inhibitory êB(IêB) which masks the leukin 6 (IL-6) in nasal epithelial cells.15 nuclear translocation signal and so prevents A conserved cysteine residue has been 10 NF-êB from entering the nucleus (fig 1). shown to be critical for both optimal DNA Upon cell stimulation—for example, by binding and redox regulation of NF-êB on September 30, 2021 by guest. Protected copyright. cytokines—specific kinases phosphorylate the protein.18 Reactive oxygen intermediates IêB-á (IêB kinase complex) and the p105/p65 (ROIs) have been recognised as important complex leading to their ubiquitination (trans- inducers of gene expression via NF-êB and fer of the ubiquitin molecule).11 Ubiquitination AP-1.19 Many of the agents that activate of p105 results in an increase in the rate at NF-êB, such as TNF-á, IL-1â, lipopolysaccha- which p105 is processed to p50, whereas ubiq- ride (LPS), and ultraviolet (UV) irradiation, uitination of IêB-á serves as a signal to the also cause an increase in the cellular produc- proteasome complex (proteolytic enzymes) to tion of ROIs by mitochondria.20 ROIs have degrade rapidly and completely the IêB unit in been directly implicated as second messengers the cytoplasm.12 This critical release of NF-êB in the activation of NF-êB, based upon the (p65/p50) from IêB results in the translocation ability of oxidants to activate NF-êB by oxida- tion of its cysteine-SH group or by ubiquitina- of active p65/p50 into the nucleus where it 21 22 binds to specific motifs in the promoter regions tion and proteolysis. In addition, hyperoxia, ozone,23 and hydrogen peroxide (H O ),24 iron of target genes. The p50 subunit within the 2 2 catalysed lipid peroxidation,25 or depletion of p50/p65 heterodimer greatly facilitates DNA reduced glutathione (GSH), and subsequent binding, whereas the p65 subunit is required 10 increases in cytosolic
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