Prostaglandins and chronic inflammation

doi:10.1016/j.tips.2012.02.004

Trends in Pharmacological Sciences

Volume 33, Issue 6, June 2012, Pages 304-311

https://doi.org/10.1016/j.tips.2012.02.004 Get rights and content

Chronic inflammation is the basis of various chronic illnesses including cancer and vascular diseases. However, much has yet to be learned how inflammation becomes chronic. Prostaglandins (PGs) are well established as mediators of acute inflammation, and recent studies in experimental animals have provided evidence that they also function in transition to and maintenance of chronic inflammation. One role PGs play in such processes is amplification of cytokine signaling. As such, PGs can facilitate acquired immunity and induce long-lasting immune inflammation. PGs also contribute to chronic inflammation by making a positive feedback loop and/or by inducing chemokines and recruiting inflammatory cells to alternate active cell populations at affected sites. PGs also contribute to tissue remodeling as seen in angiogenesis and fibrosis. Although such roles of PGs should be verified in human diseases, these findings suggest that PG signaling is a promising therapeutic target of chronic inflammatory diseases.

Section snippets

Involvement of PGs in transition from acute inflammation to chronic inflammation?

Inflammation is triggered by various types of tissue insults, induces local reddening, heat, swelling, pain and fever, and mostly subsides in a few days. However, inflammation often persists and becomes chronic. Growing evidence now suggests involvement of chronic inflammatory processes in pathogenesis of a variety of diseases including cancer [1], metabolic syndrome [2] and vascular diseases [3]. In these disorders, abundant infiltration of inflammatory cells and expression of various

PGs as a cytokine amplifier

Because COX-2 can be induced by lipopolysaccharide (LPS) and proinflammatory cytokines such as interleukin (IL)-1β and IL-6, and COX-1 is constitutively expressed irrespectively of these stimuli, PGs are believed to be formed either independently or downstream of cytokines and innate immunity and to elicit inflammatory symptoms. However, recent studies have revealed that PGs often work with cytokines and pathogen- or damage-associated molecular patterns (PAMPs and DAMPs) in various inflammatory

PGs in acquired immunity and immune inflammation

Acquired immunity is initiated by processing and presentation of antigen by dendritic cells (DCs) to naïve T cells, which are then differentiated to specific T cell subsets. The type of immune response is dependent on which T cell subset is induced to a particular antigen. Two distinct subsets of helper T cells, Th1 and Th17, which are characterized by production of interferon-γ (IFN-γ) and IL-17, respectively [11], are important cell populations that contribute to pathogenesis of various

PGE₂ in a positive feedback loop for inflammation

One possible mechanism for sustaining inflammation is a positive feedback loop to amplify the initial signal. Indeed, the presence of such a positive feedback loop involving PGs and its contribution to pathogenesis have been shown in animal models of chronic inflammatory diseases such as intracranial aneurysm (IA) and cancer. IA is a regional bulging of intracranial arteries (mostly at their bifurcation) and is histologically characterized by arterial wall degeneration, inflammatory cell

PGs and recruitment of inflammatory cells

At inflammatory sites, abundant infiltration of inflammatory cells such as neutrophils, eosinophils and macrophages is seen, and recruitment of these cells is mostly carried out by expression of chemokines. There is now substantial evidence that PGs are involved in induction of chemokines and resultant infiltration of inflammatory cells at the inflamed site (Figure 2, Figure 3). For example, as discussed above, the PGI₂–IP signaling synergizes with IL-1β in CIA to augment expression of CXCL7, a

PGs and tissue remodeling

If inflammation does not subside, it often leads to tissue remodeling. Tissue remodeling includes tissue metaplasia, granulation, angiogenesis and fibrosis, and roles of PGs in these processes have been reported (Figure 4). PGs, depending on their type, involved tissues and contexts, either facilitate or suppress tissue remodeling. For example, in the OVA-induced allergic asthma model, various genes associated with tissue remodeling (including the ADAM family of tissue proteases and goblet cell

Concluding remarks

In this review, we have discussed the roles of PGs in various animal models of chronic inflammation. Because the primary focus of this review is the role of PGs in transition to and maintenance of chronic inflammation, we have chosen recent finding pertinent to this role and discussed their implication. From the findings discussed here, it is now clear that PGs function as more than acute inflammatory mediators, and are involved in various aspects of chronic inflammation. However, in addition

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Trends in Pharmacological Sciences

ReviewProstaglandins and chronic inflammation

Section snippets

Involvement of PGs in transition from acute inflammation to chronic inflammation?

PGs as a cytokine amplifier

PGs in acquired immunity and immune inflammation

PGE2 in a positive feedback loop for inflammation

PGs and recruitment of inflammatory cells

PGs and tissue remodeling

Concluding remarks

J. Neuroimmunol.

Am. J. Pathol.

Trends Immunol.

Blood

Lancet

Cell

Lancet

Mutat. Res.

Cancer Cell

Am. J. Pathol.

J. Biol. Chem.

Biomed. Pharmacother.

Cell Metab.

Prostaglandins Leukot. Essent. Fatty Acids

Inflammation meets cancer, with NF-κB as the matchmaker

Nat. Immunol.

Type 2 diabetes as an inflammatory disease

Nat. Rev. Immunol.

Translating molecular discoveries into new therapies for atherosclerosis

Nature

Prostanoid receptors

Chem. Rev.

Prostanoids and inflammation: a new concept arising from receptor knockout mice

J. Mol. Med. (Berl.)

Fever, inflammation, pain and beyond: prostanoid receptor research during these 25 years

FASEB J.

Prostacyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis

J. Exp. Med.

Predominance of cyclooxygenase 1 over cyclooxygenase 2 in the generation of proinflammatory prostaglandins in autoantibody-driven K/BxN serum-transfer arthritis

Arthritis Rheum.

Prostaglandin E signaling and bacterial infection recruit tumor-promoting macrophages to mouse gastric tumors

Gastroenterology

Prostaglandin E2-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion

Nat. Med.

Interleukin-17 and type 17 helper T cells

N. Engl. J. Med.

Increased expression of interleukin 17 in inflammatory bowel disease

Gut

Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis

Nat. Med.

The immunological and genetic basis of inflammatory bowel disease

Nat. Rev. Immunol.

IL-17 and Th17 cells

Annu. Rev. Immunol.

A rush to judgment on Th17

J. Exp. Med.

Prostaglandin E2 inhibits production of Th1 lymphokines but not of Th2 lymphokines

J. Immunol.

A novel antagonist of the prostaglandin E2 EP4 receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models

Br. J. Pharmacol.

Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling

J. Exp. Med.

Prostaglandin E2 enhances Th17 responses via modulation of IL-17 and IFN-gamma production by memory CD4+ T cells

Eur. J. Immunol.

Review
Prostaglandins and chronic inflammation

PGE₂ in a positive feedback loop for inflammation

Prostacyclin-IP signaling and prostaglandin E₂-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis

Prostaglandin E₂-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion

Prostaglandin E₂ inhibits production of Th1 lymphokines but not of Th2 lymphokines

A novel antagonist of the prostaglandin E₂ EP4 receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models

Prostaglandin E₂ regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling

Prostaglandin E₂ enhances Th17 responses via modulation of IL-17 and IFN-gamma production by memory CD4⁺ T cells