Review article: Chemokine production by intestinal epithelial cells: a therapeutic target in inflammatory bowel disease?

The intestinal epithelium plays an important role in the recognition of pathogenic organisms and in the recruitment of inflammatory cells to the mucosa. Epithelial chemokine production may constitute a key target in future therapies for inflammatory bowel disease (IBD). Chemokines are divided into two subfamilies, the C-C family and C-X-C family. Most C-C chemokines target mononuclear cells and many C-X-C chemokines attract neutrophils. Interleukin-8 (IL-8), a C-X-C chemokine, acts as a motor for the recruitment of neutrophils into the non-inflamed mucosa and is present in both enterocytes and mucosal inflammatory cells. Epithelial cells may be the first to signal the presence of pathogens, as well as contributing to IL-8 production in IBD. Data have also shown that intestinal epithelial cells are able to respond to IL-1β and tumour necrosis factor-alpha (TNF-α) at concentrations known to occur in the inflamed mucosa. Monocyte chemotactic protein-1 (MCP-1), a member of the C-C chemokine family, is noticeably increased in IBD. These data show that C-X-C and C-C chemokines are equally important properties of mucosal epithelial cells. The effects of two anti-inflammatory drugs (dexamethasone and cyclosporin) on chemokine production are significantly different and this provides a rationale for combination therapy.     

Release of nerve growth factor by human pulmonary epithelial cells: role in airway inflammatory diseases

Elevated levels of nerve growth factor (NGF) have been detected in the bronchoalveolar lavage fluid of patients with asthma. However, the source of this enhanced mediator production is not known. Here, we investigate the production of NGF from a human airway epithelial cell line (A549). Under basal conditions, A549 cells generated NGF in a time-dependent fashion. However, basal release was significantly augmented in a concentration-dependent manner in cells treated with interleukin-1beta (IL-1beta) or tumour necrosis factor-alpha (TNF-alpha) and inhibited by dexamethasone. These data suggest that NGF released from structural cells may be an important target for the anti-inflammatory effects of steroids in asthma therapy.     

Microecology as a target for therapeutic intervention in inflammatory bowel disease

The gastrointestinal tract is populated by several hundred grams of bacteria. Recognition of the symbiosis between bacteria and host is drawing particular attention to the implications of bacteria in human health. Probiotics are living microorganisms that upon ingestion in certain numbers exert health benefits. Prebiotics are non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth or activity of a limited number of gut bacteria. In inflammatory bowel disease (IBD), the gut flora is the key factor driving the inflammatory process that leads to intestinal lesions. Interaction of certain commensal bacteria with the gut mucosa triggers mucosal inflammation. However, certain probiotic strains are able to downregulate inflammatory pathways. Restoring the microbial balance with prebiotics and probiotics offers promise for the control of IBD.     

Regulation of kinin receptors in airway epithelial cells by inflammatory cytokines and dexamethasone

The two kinin receptors, B(1) and B(2), are upregulated in inflammation and may play a role in diseases such as asthma. In pulmonary A549 cells, TNF-alpha or interleukin-1 beta dramatically increased bradykinin B(1) and B(2) receptor mRNA expression and this response was prevented by dexamethasone. In primary human bronchial epithelial cells, bradykinin B(1) receptor mRNA expression showed a similar trend, whereas bradykinin B(2) receptor showed almost constitutive expression. Radioligand-binding studies revealed significant increases in bradykinin B(2) receptor protein expression following both interleukin-1 beta and TNF-alpha treatment of A549 cells; however, no evidence was found for bradykinin B(1) receptor. Functionally, the bradykinin B(2) receptor ligand, bradykinin, but not the B(1) ligand, des-Arg(10)-kallidin, produced a marked increase in prostaglandin E(2) release when administered following interleukin-1 beta treatment. Arachidonic acid release in response to bradykinin was markedly enhanced by prior incubation with interleukin-1 beta and this was prevented by the prior addition of dexamethasone.     

Gelsolin as therapeutic target in Alzheimer's disease

Importance of the field: Fibrillar amyloid beta-protein (Aβ) is a major component of amyloid plaques in the brains of individuals with Alzheimer's disease (AD). However, a comprehensive explanation of the mechanisms leading to brain amyloidosis is still pending. Previous studies have identified the anti-amyloidogenic role of gelsolin in AD. Gelsolin can reduce amyloid burden by acting as an inhibitor of Aβ fibrillization, and as an antioxidant and anti-apoptotic protein.

Areas covered in this review: Recent evidence indicates reduced brain gelsolin levels in AD. Therefore, a better understanding of the roles of gelsolin in AD pathology, particularly those related with cognition, is required.

What the reader will gain: Most of the information reviewed here relates to experimental studies. However, gelsolin may progress from the present evidence to preclinical and clinical applications. In addition, a greater insight into the environmental factors contributing to abnormally reduced gelsolin function in AD brains may become crucial for the development of much needed disease-modifying strategies.

Take home message: Because, the efficacy of available medicines is still poor, there is an urgent need for novel AD treatments. In this sense, gelsolin could play an important role.     

Induction of the inflammatory regulator A20 by gibberellic acid in airway epithelial cells

Background and Purpose

NF‐κB‐driven inflammation is negatively regulated by the zinc finger protein A20. Gibberellic acid (GA ₃) is a plant‐derived diterpenoid with documented anti‐inflammatory activity, which is reported to induce A20‐like zinc finger proteins in plants. Here, we sought to investigate the anti‐inflammatory effect of GA ₃ in airway epithelial cells and determine if the anti‐inflammatory action relates to A20 induction.

Experimental Approach

Primary nasal epithelial cells and a human bronchial epithelial cell line (16HBE14o‐) were used. Cells were pre‐incubated with GA ₃, stimulated with P seudomonas aeruginosa  LPS; IL‐6 and IL‐8 release, A20, NF‐κB and IκBα expression were then evaluated. To determine if any observed anti‐inflammatory effect occurred via an A20‐dependent mechanism, A20 was silenced using siRNA.

Key Results

Cells pre‐incubated with GA ₃ had significantly increased levels of A20 mRNA (4 h) and protein (24 h), resulting in a significant reduction in IL‐6 and IL‐8 release. This effect was mediated via reduced IκBα degradation and reduced NF‐κB (p65) expression. Furthermore, the anti‐inflammatory action of GA ₃ was abolished in A20‐silenced cells.

Conclusions and Implications

We showed that A20 induction by GA ₃ attenuates inflammation in airway epithelial cells, at least in part through its effect on NF‐κB and IκBα. GA ₃ or gibberellin‐derived derivatives could potentially be developed into anti‐inflammatory drugs for the treatment of chronic inflammatory diseases associated with A20 dysfunction.

Linked Articles

This article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2016.173.issue-4

Abbreviations

16HBE14o‐

human bronchial epithelial cells

CF

cystic fibrosis

Dex

dexamethasone

GA₃

gibberellic acid 3

NEMO

NF‐κB essential modulator

OTU

ovarian tumour domain

PNEC

primary nasal epithelial cell

TLR4

toll‐like receptor 4

TRAF6

TNF receptor‐associated factor 6

Tables of Links

A pharmacological approach to enhancing the therapeutic index of corticosteroids in airway inflammatory disease

Inhaled corticosteroids are highly effective agents for the treatment of asthma and chronic obstructive pulmonary disease. Although local delivery to the lung has led to significant progress towards minimising side effects associated with systemic exposure, additional opportunities exist for further enhancement of the therapeutic index. Recent developments in the molecular and structural understanding of corticosteroid biology have made it increasingly clear that novel corticosteroids with intrinsically different pharmacology can be designed.     

TIM-3 as a therapeutic target in human inflammatory diseases

T-cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) was the first, and is presently the only, surface molecule that can specifically identify T_H1 cells in both mice and humans. Engagement of Tim-3 by its ligand galectin-9 negatively regulates IFN-γ secretion and influences the ability to induce T cell tolerance in both mice and man. Numerous studies have demonstrated that Tim-3 influences autoimmune diseases, including diabetes and multiple sclerosis, and its role in other inflammatory diseases including allergies and cancer is beginning to become clear.     

TIM-3 as a therapeutic target in human inflammatory diseases

T-cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) was the first, and is presently the only, surface molecule that can specifically identify T(H)1 cells in both mice and humans. Engagement of Tim-3 by its ligand galectin-9 negatively regulates IFN-gamma secretion and influences the ability to induce T cell tolerance in both mice and man. Numerous studies have demonstrated that Tim-3 influences autoimmune diseases, including diabetes and multiple sclerosis, and its role in other inflammatory diseases including allergies and cancer is beginning to become clear.     

Extracellular HMGB1 as a therapeutic target in inflammatory diseases

Introduction: High-mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that promotes inflammation when released extracellularly after cellular activation, stress, damage or death. HMGB1 operates as one of the most intriguing molecules in inflammatory disorders via recently elucidated signal and molecular transport mechanisms. Treatments based on antagonists specifically targeting extracellular HMGB1 have generated encouraging results in a wide number of experimental models of infectious and sterile inflammation. Clinical studies are still to come.

Areas covered: We here summarize recent advances regarding pathways for extracellular HMGB1 release, receptor usage, and functional consequences of post-translational modifications. The review also addresses results of preclinical HMGB1-targeted therapy studies in multiple inflammatory conditions and outlines the current status of emerging clinical HMGB1-specific antagonists.

Expert opinion: Blocking excessive amounts of extracellular HMGB1, particularly the disulfide isoform, offers an attractive clinical opportunity to ameliorate systemic inflammatory diseases. Therapeutic interventions to regulate intracellular HMGB1 biology must still await a deeper understanding of intracellular HMGB1 functions. Future work is needed to create more robust assays to evaluate functional bioactivity of HMGB1 antagonists. Forthcoming clinical studies would also greatly benefit from a development of antibody-based assays to quantify HMGB1 redox isoforms, presently assessed by mass spectrometry methods.     

Estrogen as a new therapeutic target for asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) affect the lives of a large portion of the population and can lead to morbidity and mortality. In many women, the incidence and severity of asthma exacerbations vary along their menstrual cycle. Estrogen, a natural occurring hormone, affects differently many of the cell types that are involved in asthma, including macrophages, eosinophils, neutrophils, lymphocyte, mast cells, fibroblasts, epithelial and smooth muscle cells. By binding to its receptors on the plasma or nuclear membrane, estrogen affects the expression of a plethora of proteins that are involved in the pathogenesis of asthma and COPD. In this review we will summarize the current knowledge of the role of estrogen in the expression, production and secretion of inflammatory agents that are involved in asthma and COPD and its potential therapeutic role in these diseases.     

Topical delivery of therapeutic agents in the treatment of inflammatory bowel disease

For targeting local and systemic inflammatory processes in inflammatory bowel disease (IBD) therapeutic agents of first choice (e.g. aminosalicylates, corticosteroids) have been developed in special galenic forms to accomplish the topical delivery of the active compounds to the terminal ileum (Crohn's disease) and/or the colon (Crohn's disease and ulcerative colitis). However, it has to be realized that intestinal physiology (e.g. motility, intraluminal pH profiles), extent and pattern of IBD as well as drug disposition demonstrate large interindividual differences resulting in variable clinical response rates between about 35% and 75%. 5-Aminosalicylate (5-AS) can be delivered to the colon either by azo-prodrugs (e.g. sulfasalazine, olsalazine or balsalazide) or by direct rectal administration of 5-AS in form of enemas, foam or suppositories. Such formulations will be only effective in patients with ulcerative colitis (UC). Various slow/controlled release preparations of 5-AS have been developed for oral use. Some of them (e.g. Pentasa, Salofalk) release sufficient 5-AS already in the small bowel which could provide some additional benefit in Crohn's disease (CD). As urinary and faecal recoveries of total 5-AS are similar for all oral formulations, no major clinical differences can be expected. Extent of the disease, profile of adverse effects and patient's acceptance provide some guidance for selection of the particular agent. Rectal installation of several glucocorticosteroids has been employed for many years. More recently scientific and clinical interest has been focused on budesonide which is extensively presystemically metabolized in the intestinal wall and the liver. Therefore, its systemic availability is low (10-15%) independent whether budesonide is administered orally as controlled release formulation in patients with CD or rectally as enema in patients with UC. Numerous pharmacokinetic and clinical studies have documented the anticipated topical delivery and clinical efficacy of this corticosteroid without serious side effects such as cushingoid features. It can be assumed that for any novel therapeutic principle in IBD the approach of topical delivery will be also tried.