Prostaglandin I2 Suppresses Proinflammatory Chemokine Expression, CD4 T Cell Activation, and STAT6-Independent Allergic Lung Inflammation

Abstract

Allergic airway diseases are immune disorders associated with heightened type 2 immune responses and IL-5 and IL-13 production at the site of inflammation. We have previously reported that cyclooxygenase (COX) inhibition by indomethacin augmented allergic airway inflammation in a STAT6-independent manner. However, the key COX product(s) responsible for restraining indomethacin-mediated STAT6-independent allergic inflammation is unknown. In this study, using the mouse model of OVA-induced allergic airway inflammation, we identified that PGI2 receptor (IP) signaling was critical for indomethacin-induced, STAT6-independent proallergic effects. We demonstrated that IP deficiency increased inflammatory cell infiltration, eosinophilia, and IL-5 and IL-13 expression in the lung in a STAT6-independent manner. The augmented STAT6-independent allergic inflammation correlated with enhanced primary immune responses to allergic sensitization and elevated production of multiple inflammatory chemokines (CCL11, CCL17, CCL22, and CXCL12) in the lung after allergen challenge. We also showed that the PGI2 analogue cicaprost inhibited CD4 T cell proliferation and IL-5 and IL-13 expression in vitro, and IP deficiency diminished the stimulatory effect of indomethacin on STAT6-independent IL-5 and IL-13 responses in vivo. The inhibitory effects of PGI2 and the IP signaling pathway on CD4 T cell activation, inflammatory chemokine production, and allergic sensitization and airway inflammation suggest that PGI2 and its analogue iloprost, both Food and Drug Administration–approved drugs, may be useful in treating allergic diseases and asthma. In addition, inhibiting PGI2 signaling by drugs that either block PGI2 production or restrain IP signaling may augment STAT6-independent pathways of allergic inflammation.

Genetic variant in CXCL12 gene raises susceptibility to HPV infection and squamous intraepithelial lesions development: a case-control study

“…CXCL12 has been considered as a standard proinflammatory molecule for a long time, since it attracts leukocytes to inflammatory sites contributing to their activation [ 9 , 29 ]. Data have suggested that HPV pre-cancerous lesion depend on both the suppression of cellular immunity, driven by the Th1 response and the development of the immunosuppressive Treg profile for neoplastic progression [ 30 ].…”

“…Prolonged inflammation may facilitate carcinogenesis by providing an ideal microenvironment for tumor growth and development [ 8 ]. Several chemokines play important role in inflammation process, including CXCL12 due to its pro-inflammatory characteristic, acting as chemoattractant to immune cells such as lymphocyte [ 9 ].…”

Prostaglandin‐cytokine crosstalk in chronic inflammation

“…Zhou et al . confirmed these phenotypes of IP‐deficient mice and further revealed that these phenotypes caused by IP‐deficiency are not dependent on STAT6 (Zhou et al ., ). Similar to IP receptor‐deficient mice, EP 2 receptor‐deficient mice also show an exaggerated OVA‐induced airway inflammation accompanied by increased IL‐13 production, with higher serum IgE levels, and the administration of misoprostol during the sensitization process suppressed the production of IgE and attenuated the inflammatory response (Zasłona et al ., ).…”

“…Indeed, mice deficient in IP receptors exhibited significantly higher serum IgE levels compared to wild type mice and showed significantly enhanced allergic inflammation of the lung in an ovalbumin (OVA)-induced allergic asthma model (Nagao et al, 2003). Zhou et al confirmed these phenotypes of IP-deficient mice and further revealed that these phenotypes caused by IPdeficiency are not dependent on STAT6 (Zhou et al, 2016b). Similar to IP receptor-deficient mice, EP 2 receptordeficient mice also show an exaggerated OVA-induced airway inflammation accompanied by increased IL-13 production, with higher serum IgE levels, and the administration of misoprostol during the sensitization process suppressed the production of IgE and attenuated the inflammatory response (Zasłona et al, 2014).…”

Anti- Versus Pro-Inflammatory Metabololipidome Upon Cupping Treatment

“…Deficiencies of ω-3 PUFAs contribute to several chronic inflammatory diseases, including obesity and diabetes [16]. Leukotriene B 4 (LTB 4 ), 5-HETE and prostaglandin E 2 (PGE 2 ) are pro-inflammatory, while lipoxin A 4 (LXA 4 ) and PGI 2 are anti-inflammatory metabolites derived from AA, an ω-6 PUFA [13, 17, 18]. These relationships between tissue homeostasis and lipid metabolism inspire us to address whether cupping treatment modulates the metabolic balance between pro- and anti-inflammatory PUFAs.…”