Prostaglandin I2 analogs inhibit Th1 and Th2 effector cytokine production by CD4 T cells

Zhou, Weisong; Blackwell, Timothy S.; Goleniewska, Kasia; O’Neal, Jamye F.; FitzGerald, Garret A.; Lucitt, Margaret B.; Breyer, Richard M.; Peebles, R. Stokes

doi:10.1189/jlb.0606375

Cited by 79 publications

(88 citation statements)

References 55 publications

(79 reference statements)

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“…Independent studies corroborated these findings by demonstrating that iloprost suppresses CCL17, CCL11, lung eosinophil accumulation and the recruitment of CD4+ Th2 to the airways in asthma models [40,41]. PGI 2 counteracts the capacity of T-cells to produce the pro-inflammatory cytokines IL-12, p70, TNF-a, MIP-1a, MCP-1 and IL-6 [42,43]. PGI 2 has also been demonstrated to reduce lipopolysaccharide-induced cytokine production in leukocytes through the inhibition of nuclear factor-kB [44].…”

supporting

confidence: 62%

Fibrocytes: potential new therapeutic targets for pulmonary hypertension?

Stenmark¹,

Frid²,

Yeager³

2010

Eur Respir J

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supporting

confidence: 62%

Fibrocytes: potential new therapeutic targets for pulmonary hypertension?

Stenmark¹,

Frid²,

Yeager³

2010

Eur Respir J

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“…2/2 mice, as previously described (34) and detailed in the online supplement. Purified CD4 1 cells were positively selected and then polarized down the T helper (Th) type 0, Th1, Th2, or Th17 pathway, as previously described (35,36).…”

Section: T Cell Isolation and Polarizationmentioning

confidence: 99%

“…Bone marrow from WT and gp91phox 2/2 mice was harvested and then cultured for 8 days, as previously described (34) and detailed in the online supplement.…”

Section: Dendritic Cell Culturementioning

confidence: 99%

Deficiency of gp91phox Inhibits Allergic Airway Inflammation

Sevin

Newcomb

Toki

et al. 2013

Am J Respir Cell Mol Biol

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Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a multienzyme complex, is the major source for production of reactive oxygen species (ROS). ROS are increased in allergic diseases, such as asthma, but the role of ROS in disease pathogenesis remains uncertain. We hypothesized that mice unable to generate ROS via the NADPH oxidase pathway would have decreased allergic airway inflammation. To test this hypothesis, we studied gp91phox 2/2 mice in a model of allergic airway inflammation after sensitization and challenge with ovalbumin. Serum, bronchoalveolar lavage fluid, and lungs were then examined for evidence of allergic inflammation. We found that mice lacking a functional NADPH oxidase complex had significantly decreased ROS production and allergic airway inflammation, compared with wild-type (WT) control animals. To determine the mechanism by which allergic inflammation was inhibited by gp91phox deficiency, we cultured bone marrowderived dendritic cells from WT and gp91phox 2/2 mice and activated them with LPS. IL-12 expression was significantly increased in the gp91phox 2/2 bone marrow-derived dendritic cells, suggesting that the cytokine profile produced in the absence of gp91phox enhanced the conditions leading to T helper (Th) type 1 differentiation, while inhibiting Th2 polarization. Splenocytes from sensitized gp91phox 2/2 animals produced significantly less IL-13 in response to ovalbumin challenge in vitro compared with splenocytes from sensitized WT mice, suggesting that NADPH oxidase promotes allergic sensitization. In contrast, inflammatory cytokines produced by T cells cultured from WT and gp91phox 2/2 mice under Th0, Th1, Th2, and Th17 conditions were not significantly different. This study demonstrates the importance of NADPH oxidase activity and ROS production in a murine model of asthma.Keywords: asthma; allergic airway inflammation; gp91phox; reactive oxygen species; NADPH oxidase Asthma is a significant health problem, affecting up to 300 million children and adults around the world (1). In the United States alone, costs associated with asthma exceed $50 billion each year due to health care use and lost productivity (2). The prevalence of this disease is increasing, without clear etiology (3, 4). Chronic inflammation of the airways is a hallmark of the disease (5), and yet, despite widespread research, the mechanisms of persistent allergic airway inflammation are poorly understood.Reactive oxygen species (ROS) are increased in allergic diseases, such as asthma, and ROS production is associated with airway inflammation and airway hyperresponsiveness (6). Breath condensates from subjects with asthma have been shown to contain increased hydrogen peroxide, an ROS, and 8-isoprostane, an F 2 -isoprostane that is a marker of oxidative stress, compared to control subjects without asthma (7-9). In addition, increased levels of peroxidation products are present in the serum, urine, and lung tissue of patients with asthma compared with those without asthma (10-12). Mice with allergic lung inf...

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“…Indeed, studies performed by our laboratory and other investigators revealed that the COX product prostaglandin (PG) I 2 , which signals through the G protein-coupled receptor IP, was a critical inhibitor of the adaptive immune response in animal models of allergic lung inflammation (14)(15)(16)(17)(18)(19)(20). IP predominantly couples to a G s -type G protein, leading to an increase in cAMP (21).…”

mentioning

confidence: 99%

Prostaglandin I₂Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses

Zhou

Toki

Zhang

et al. 2016

Am J Respir Crit Care Med

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Rationale: Group 2 innate lymphoid cells (ILC2s) robustly produce IL-5 and IL-13, cytokines central to the asthma phenotype; however, the effect of prostaglandin (PG) I 2 on ILC2 function is unknown.Objectives: To determine the effect of PGI 2 on mouse and human ILC2 cytokine expression in vitro and the effect of endogenous PGI 2 and the PGI 2 analog cicaprost on lung ILC2s in vivo.Methods: Flow-sorted bone marrow ILC2s of wild-type (WT) and PGI 2 receptor-deficient (IP 2/2 ) mice were cultured with IL-33 and treated with the PGI 2 analog cicaprost. WT and IP 2/2 mice were challenged intranasally with Alternaria alternata extract for 4 consecutive days to induce ILC2 responses, and these were quantified. Prior to A. alternata extract, challenged WT mice were treated with cicaprost. Human flow-sorted peripheral blood ILC2s were cultured with IL-33 and IL-2 and treated with the PGI 2 analog cicaprost. Measurement and Main Results:We demonstrate that PGI 2 inhibits IL-5 and IL-13 protein expression by IL-33-stimulated ILC2s purified from mouse bone marrow in a manner that was dependent on signaling through the PGI 2 receptor IP. In a mouse model of 4 consecutive days of airway challenge with an extract of A. alternata, a fungal aeroallergen associated with severe asthma exacerbations, endogenous PGI 2 signaling significantly inhibited lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5-and IL-13-expressing ILC2s, as well as the mean fluorescence intensity of IL-5 and IL-13 staining. In addition, exogenous administration of a PGI 2 analog inhibited Alternaria extract-induced lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5-and IL-13-expressing ILC2s and the mean fluorescence intensity of IL-5 and IL-13 staining. Finally, a PGI 2 analog inhibited IL-5 and IL-13 expression by human ILC2s that were stimulated with IL-2 and IL-33.Conclusions: These results suggest that PGI 2 may be a potential therapy to reduce the ILC2 response to protease-containing aeroallergens, such as Alternaria.

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Prostaglandin I2 analogs inhibit Th1 and Th2 effector cytokine production by CD4 T cells

Cited by 79 publications

References 55 publications

Fibrocytes: potential new therapeutic targets for pulmonary hypertension?

Fibrocytes: potential new therapeutic targets for pulmonary hypertension?

Deficiency of gp91phox Inhibits Allergic Airway Inflammation

Prostaglandin I₂Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses

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Prostaglandin I2 analogs inhibit Th1 and Th2 effector cytokine production by CD4 T cells

Cited by 79 publications

References 55 publications

Fibrocytes: potential new therapeutic targets for pulmonary hypertension?

Fibrocytes: potential new therapeutic targets for pulmonary hypertension?

Deficiency of gp91phox Inhibits Allergic Airway Inflammation

Prostaglandin I2Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses

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Prostaglandin I₂Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses