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

Published on Sep 1, 2016in Journal of Immunology4.886
· DOI :10.4049/JIMMUNOL.1501063
Weisong Zhou23
Estimated H-index: 23
(Vandy: Vanderbilt University),
Jian Zhang22
Estimated H-index: 22
(Vandy: Vanderbilt University)
+ 8 AuthorsR. Stokes Peebles58
Estimated H-index: 58
(Vandy: Vanderbilt University)
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 PGI 2 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 PGI 2 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 PGI 2 and the IP signaling pathway on CD4 T cell activation, inflammatory chemokine production, and allergic sensitization and airway inflammation suggest that PGI 2 and its analogue iloprost, both Food and Drug Administration–approved drugs, may be useful in treating allergic diseases and asthma. In addition, inhibiting PGI 2 signaling by drugs that either block PGI 2 production or restrain IP signaling may augment STAT6-independent pathways of allergic inflammation.
📖 Papers frequently viewed together
116 Citations
#1Huilong Chen (HUST: Huazhong University of Science and Technology)H-Index: 13
#2Xiangqin Xu (HUST: Huazhong University of Science and Technology)H-Index: 4
Last. Weining Xiong (HUST: Huazhong University of Science and Technology)H-Index: 19
view all 11 authors...
Accumulating evidence suggests that chemokine (C-X-C motif) ligand 12 (CXCL12) and its receptor chemo- kine (C-X-C motif) receptor 4 (CXCR4) may contribute to the pathogenesis of allergic asthma. However, the underlying molecular mechanisms remain to be fully understood. T-helper 17 cells (Th17) and T-cytotoxic 17 cells (Tc17) have been implicated in the development of several allergic disor- ders, including asthma. The present study aimed to explore the association between CXCL12 signaling and ...
17 CitationsSource
#1Ming-Kai Tsai (Meiho University)H-Index: 5
#2Chong-Chao Hsieh (KMU: Kaohsiung Medical University)H-Index: 6
Last. Chih-Hsing Hung (KMU: Kaohsiung Medical University)H-Index: 11
view all 7 authors...
Chemokines play essential roles during inflammatory responses and in pathogenesis of inflammatory diseases. Monocyte chemotactic protein-1 (MCP-1) is a critical chemokine in the development of atherosclerosis and acute cardiovascular syndromes. MCP-1, by its chemotactic activity, causes diapedesis of monocytes from the lumen to the subendothelial space that leads to atherosclerotic plaque formation. Prostaglandin I2 (PGI2) analogs are used clinically for patients with pulmonary hypertension and ...
6 CitationsSource
#1Eva Hoi Ching Tang (HKU: University of Hong Kong)H-Index: 17
#2Yin Cai (HKU: University of Hong Kong)H-Index: 11
Last. Aimin Xu (HKU: University of Hong Kong)H-Index: 99
view all 10 authors...
Inflammation of adipose tissue induces metabolic derangements associated with obesity. Thus, determining ways to control or inhibit inflammation in adipose tissue is of clinical interest. The present study tested the hypothesis that in mouse adipose tissue, endogenous prostaglandin E2 (PGE2) negatively regulates inflammation via activation of prostaglandin E receptor 4 (EP4). PGE2 (5–500nM) attenuated lipopolysaccharide-induced mRNA and protein expression of chemokines, including interferon-γ-in...
20 CitationsSource
#1Weisong Zhou (Vandy: Vanderbilt University)H-Index: 23
#2Kasia Goleniewska (Vandy: Vanderbilt University)H-Index: 21
Last. R. Stokes Peebles (Vandy: Vanderbilt University)H-Index: 58
view all 14 authors...
Background The prevalence of allergic diseases has doubled in developed countries in the past several decades. Cyclooxygenase (COX)-inhibiting drugs augmented allergic diseases in mice by increasing allergic sensitization and memory immune responses. However, whether COX inhibition can promote allergic airway diseases by inhibiting immune tolerance is not known. Objective To determine the role of the COX pathway and prostaglandin I 2 (PGI 2 ) signaling through the PGI 2 receptor (IP) in aeroalle...
14 CitationsSource
#1Amrita Saha (CU: University of Calcutta)H-Index: 4
#2Arunima Biswas (CSIR: Council of Scientific and Industrial Research)H-Index: 7
Last. Anindita Ukil (CU: University of Calcutta)H-Index: 16
view all 6 authors...
Persistence of intracellular infection depends on the exploitation of factors that negatively regulate the host immune response. In this study, we elucidated the role of macrophage PGE2, an immunoregulatory lipid, in successful survival of Leishmania donovani, causative agent of the fatal visceral leishmaniasis. PGE2 production was induced during infection and resulted in increased cAMP level in peritoneal macrophages through G protein–coupled E-series prostanoid (EP) receptors. Among four diffe...
41 CitationsSource
#1Ming-Kai TsaiH-Index: 5
#2Chong-Chao Hsieh (Meiho University)H-Index: 2
Last. Chih-Hsing HungH-Index: 11
view all 9 authors...
Aims Inflammation plays critical roles in atherosclerosis. Chemokines are responsible for leukocyte trafficking and involve in inflammatory diseases. Macrophage inflammatory protein 1α (MIP-1α) has been implicated in atherosclerotic lesion formation. Prostaglandin I 2 (PGI 2 ) analog, used in pulmonary hypertension, has been reported to have anti-inflammatory functions. However, little is known about its role in the MIP-1α production in human monocytes. Methods We investigated the effects of 3 c...
7 CitationsSource
#1Stacy L. Dorris (Vandy: Vanderbilt University)H-Index: 4
#2R. Stokes PeeblesH-Index: 58
Prostacyclin, or PGI2, is an end product derived from the sequential metabolism of arachidonic acid via cyclooxygenase and PGI synthase (PGIS). The receptor for PGI2, IP, can be found on a variety of cell types and signaling through this receptor exhibits broad physiological effects. Historically, PGI2 has been understood to play a role in cardiovascular health, specifically having powerful vasodilatory effects via relaxation of smooth muscle and inhibiting of platelet aggregation. For these rea...
86 CitationsSource
Rationale: Th17 cells comprise a distinct lineage of proinflammatory T helper cells that are major contributors to allergic responses. It is unknown whether cyclooxygenase (COX)-derived eicosanoids regulate Th17 cells during allergic lung inflammation.Objectives: To determine the role of COX metabolites in regulating Th17 cell differentiation and function during allergic lung inflammation.Methods: COX-1−/−, COX-2−/−, and wild-type mice were studied in an in vivo model of ovalbumin-induced allerg...
45 CitationsSource
#1Wan Wang (University of Newcastle)H-Index: 3
#2Philip M. Hansbro (University of Newcastle)H-Index: 65
Last. Ming Yang (University of Newcastle)H-Index: 65
view all 4 authors...
Background Enhanced eosinophil responses have critical roles in the development of allergic diseases. IL-5 regulates the maturation, migration and survival of eosinophils, and IL-5 and eotaxins mediate the trafficking and activation of eosinophils in inflamed tissues. CD4+ Th2 cells are the main producers of IL-5 and other cells such as NK also release this cytokine. Although multiple signalling pathways may be involved, STAT6 critically regulates the differentiation and cytokine production of T...
9 CitationsSource
#1Sylvia M. WilsonH-Index: 28
#2Neil A. SheddanH-Index: 1
Last. Mark A. GiembyczH-Index: 61
view all 4 authors...
Herein we provide evidence for the coexpression of two distinct prostacyclin (PGI 2 ) receptors (IP) on BEAS-2B human airway epithelial cells. IP receptor heterogeneity initially was suggested by the finding that the rank orders of potency of PGI 2 and three structurally similar analogs [taprostene, iloprost, 15-deoxy-16-( m -tolyl)-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC)] for the inhibition of chemokine (CXCL9 and CXCL10) release and for transcriptional activation/augmentation of cAMP...
15 CitationsSource
Cited By18
#1Oyebola O. Oyesola (UW: University of Washington)H-Index: 4
#2Elia D. Tait Wojno (UW: University of Washington)H-Index: 17
Type 2 immunity is critical for the protective and repair responses that mediate resistance to parasitic helminth infection. This immune response also drives aberrant inflammation during atopic diseases. Prostaglandins are a class of critical lipid mediators that are released during Type 2 inflammation and are integral in controlling the initiation, activation, maintenance, effector functions and resolution of Type 2 inflammation. In this review, we explore the role of the different prostaglandi...
#1Allison E. Norlander (Vandy: Vanderbilt University)H-Index: 11
#2Melissa H. Bloodworth (Vandy: Vanderbilt University)H-Index: 8
Last. R. Stokes Peebles (Vandy: Vanderbilt University)H-Index: 58
view all 19 authors...
T regulatory cells (Treg) restrain both the innate and adaptive immune systems to maintain homeostasis. Allergic airway inflammation, characterized by a type 2 (Th2) response that results from a breakdown of tolerance to innocuous environmental antigens, is negatively regulated by Treg. We previously reported that prostaglandin I2 (PGI2) promoted immune tolerance in models of allergic inflammation; however, the effect of PGI2 on Treg function was not investigated. Treg from mice deficient in the...
3 CitationsSource
#1Xiangming Sun (Harbin University of Commerce)H-Index: 4
#2Hui Song (Harbin University of Commerce)H-Index: 2
Last. Zhenduo Ding (Harbin University of Commerce)
view all 7 authors...
Abstract As a traditional Chinese medicine of invigorating the kidney, Cuscuta chinensis (CC) can be applied in improving the deficiency of kidney qi in menopausal women and regulating the level of estrogen. Previously, it was found that the ethanol extract of CC had an estrogen-like effect. In this study, the metabolic profile and metabolic pathways of rats in sham, ovariectomized model and CC groups were analyzed using UPLC-TOFMS-based metabolomics and the pattern recognition technology. The s...
#1Xavier NorelH-Index: 31
#2Yukihiko SugimotoH-Index: 81
Last. Lucie H. ClappH-Index: 33
view all 15 authors...
Prostaglandins are derived from arachidonic acid metabolism through cyclooxygenase activities. Among prostaglandins (PGs), prostacyclin (PGI2) and PGE2 are strongly involved in the regulation of homeostasis and main physiologic functions. In addition, the synthesis of these two prostaglandins is significantly increased during inflammation. PGI2 and PGE2 exert their biologic actions by binding to their respective receptors, namely prostacyclin receptor (IP) and prostaglandin E2 receptor (EP) 1-4,...
4 CitationsSource
#1Danian Dai (SYSU: Sun Yat-sen University)H-Index: 1
#2Bo Chen (Peking Union Medical College)H-Index: 11
Last. Jihong Liu (SYSU: Sun Yat-sen University)H-Index: 16
view all 7 authors...
BACKGROUND Prostaglandin I2 synthase (PTGIS) is a crucial gene for the synthesis of prostaglandin I2, which has multiple roles in inflammation and immune modulation. However, studies on the prognostic value of PTGIS and its correlation with tumor-infiltrating immune cells in multiple cancers are still rare. RESULTS Multiple datasets of the Oncomine database showed that PTGIS was expressed at low levels in lung cancer and ovarian cancer compared to the levels in normal tissues. Kaplan-Meier plott...
4 CitationsSource
#1Jianguo Liu (NCU: Nanchang University)H-Index: 2
#2Xunshuo Jiang (NCU: Nanchang University)H-Index: 1
Last. Chunping Yang (NCU: Nanchang University)H-Index: 4
view all 7 authors...
Abstract Background Acute allergic nasal inflammation is very common in the clinical allergic diseases, Prostaglandin I2 (PGI2) has been found to effective in combating inflammation. Iloprost, as an analog of PGI2, whose role and mechanisms in the acute allergic nasal inflammation remains unclear. It’s necessary to elucidate the efficacy and potential mechanism of Iloprost in acute allergic nasal inflammation. Methods 36 female mice were randomly divided into DMSO group, IL 33 group, Iloprost gr...
1 CitationsSource
#1Tzu-Hsuan Wong (KMU: Kaohsiung Medical University)H-Index: 2
#2Rung-Jiun Gau (ITRI: Industrial Technology Research Institute)H-Index: 2
Last. Jau-Ling Suen (KMU: Kaohsiung Medical University)H-Index: 17
view all 7 authors...
Abstract Iloprost, a stable prostaglandin I2 (PGI2) analog, can inhibit allergic inflammation in an ovalbumin (OVA)-induced asthma model via inhibition of airway dendritic cell (DC) function. However, the underlying mechanism of PGI2 signaling-mediated immunosuppression remains unclear. This study explored whether iloprost-treated DCs can suppress inflammation by promoting antigen-specific regulatory T cell (Treg) differentiation through PGI2-G-protein-coupled receptor (IP). We established an al...
5 CitationsSource
Scleritis and other autoimmune diseases are characterized by an imbalance in the levels of pro-inflammatory and anti-inflammatory molecules with the balance tilted more towards the former due to the failure of recognition of self. The triggering of inflammatory process could be ascribed to the presence of cytoplasmic DNA/chromatin that leads to activation of cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway and enhanced expression of NF-κ...
6 CitationsSource
#1Ai Jin (NWAFU: Northwest A&F University)H-Index: 1
#2Rujuan Bao (Fourth Military Medical University)H-Index: 2
Last. Shemin Lu (Xi'an Jiaotong University)H-Index: 29
view all 9 authors...
MicroRNA‐23a (miR‐23a) was significantly upregulated in an antigen‐induced pulmonary inflammation rat model with cell type‐specific effects on bronchial epithelial cells and fibroblasts. In epithelial cells interleukin‐4 induced miR‐23a expression, and thus, decreased B cell lymphoma‐2 and induced apoptosis. In fibroblasts, thymic stromal lymphopoietin upregulated miR‐23a, which suppressed CXCL12 and CREB phosphorylation.
10 CitationsSource
#1Damian Maseda (UPenn: University of Pennsylvania)H-Index: 14
#2Emanuela Ricciotti (UPenn: University of Pennsylvania)H-Index: 27
Last. Leslie J. Crofford (Vandy: Vanderbilt University)H-Index: 79
view all 3 authors...
Abstract Prostaglandins (PG) are pleiotropic bioactive lipids involved in the control of many physiological processes, including key roles in regulating inflammation. This links PG to the modulation of the quality and magnitude of immune responses. T cells, as a core part of the immune system, respond readily to inflammatory cues from their environment, and express a diverse array of PG receptors that contribute to their function and phenotype. Here we put in context our knowledge about how PG a...
2 CitationsSource