Abstract
Chronic inflammation underlies various debilitating disorders including autoimmune, neurodegenerative, vascular and metabolic diseases as well as cancer, where aberrant activation of the innate and acquired immune systems is frequently seen. Since non‐steroidal anti‐inflammatory drugs exert their effects by inhibiting COX and suppressing PG biosynthesis, PGs have been traditionally thought to function mostly as mediators of acute inflammation. However, an inducible COX isoform, COX‐2, is often highly expressed in tissues of the chronic disorders, suggesting an as yet unidentified role of PGs in chronic inflammation. Recent studies have shown that in addition to their short‐lived actions in acute inflammation, PGs crosstalk with cytokines and amplify the cytokine actions on various types of inflammatory cells and drive pathogenic conversion of these cells by critically regulating their gene expression. One mode of such PG‐mediated amplification is to induce the expression of relevant cytokine receptors, which is typically observed in Th1 cell differentiation and Th17 cell expansion, events leading to chronic immune inflammation. Another mode of amplification is cooperation of PGs with cytokines at the transcription level. Typically, PGs and cytokines synergistically activate NF‐κB to induce the expression of inflammation‐related genes, one being COX‐2 itself, which makes PG‐mediated positive feedback loops. This signalling consequently enhances the expression of various NF‐κB‐induced genes including chemokines to macrophages and neutrophils, which enables sustained infiltration of these cells and further amplifies chronic inflammation. In addition, PGs are also involved in tissue remodelling such as fibrosis and angiogenesis. In this article, we review these findings and discuss their relevance to human diseases.
Highlights
Upon invasion of foreign pathogens or tissue damage, the innate immune system is immediately activated in response to molecules bearing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), recruits granulocytes to the injured tissue to clear pathogens, produces inflammatory mediators including proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6 and lipid mediators such as prostaglandins (PGs) and leukotrienes (LTs), and evokes an acute inflammatory process to clear the pathogens and damaged tissues
As reviewed here, substantial evidence derived from in vitro and in vivo animal model experiments suggest that PGs are significantly involved in chronic inflammation by regulating both innate and adaptive immune cells, and gene signature analysis of clinical samples as well as genomewide association study (GWAS) of patients appears to support these experimental findings
One is to induce or enhance expression of receptor(s) for the involved cytokines, which is seen in PGE2-EP2/EP4 signalling-mediated IL-12R 2 and IFN R1 induction in Th1 cells, IL23R induction in Th17 cells, PGD2-DP2 signalling-mediated ST2 and IL-17RA induction in type 2 innate lymphoid cells (ILCs) (ILC2) cells, and PGI2-PGI receptor (IP) signalling-mediated IL-1R1 induction in synoviocytes
Summary
Upon invasion of foreign pathogens or tissue damage, the innate immune system is immediately activated in response to molecules bearing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), recruits granulocytes to the injured tissue to clear pathogens, produces inflammatory mediators including proinflammatory cytokines such as tumor necrosis factor (TNF)- , interleukin (IL)-1 and IL-6 and lipid mediators such as prostaglandins (PGs) and leukotrienes (LTs), and evokes an acute inflammatory process (hours to days) to clear the pathogens and damaged tissues. Blockade of PGE2 or PGI2 production by inhibiting COX, mPGES1 or receptors by small molecular inhibitors would be effective treatment in progression of autoimmune diseases Clinical relevance of these findings to human autoimmune diseases is indicated by experimental findings that patients with autoimmune inflammatory diseases like IBD and MS had elevated levels of PGE2 in serum and the site of inflammation, e.g., the cerebrospinal fluid for MS (Mattsson et al, 2009; Prüss et al, 2013) and genetic findings from recent GWAS studies, which have identified Ptger (EP4) as a susceptible locus in a number of autoimmune diseases including inflammatory bowel disease (IBD) (Glas et al, 2012), multiple sclerosis (MS) (International Multiple Sclerosis Genetics Consortium et al, 2011), ankylosing spondylitis (AS) and allergy (Hinds et al, 2013; Parkes et al, 2013). These results suggest a crucial role for PGE2-IL-6/IL-23 crosstalk in generation of IL-22+ T cells and promoting T cell-mediated chronic inflammatory skin disease
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