A Key Role for Prostaglandin I2 in Limiting Lung Mucosal Th2, But Not Th1, Responses to Inhaled Allergen

Jaffar, Zeina; Wan, Kong‐Sang; Roberts, Kevan

doi:10.4049/jimmunol.169.10.5997

Cited by 72 publications

(118 citation statements)

References 41 publications

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“…DCs may be affected in vivo by PGs produced by neighboring cells at the sites of inflammation, leading to decreased DC activation, maturation, and function. In the model of OVA-induced allergic inflammation in the lung, multiple PGs including PGI 2 , PGE 2 , PGF 2␣ , and PGD 2 were detected in the bronchoalveolar lavage fluid (57)(58)(59). The source of PGI 2 may be endothelial cells that constitutively express PGI 2 synthase (60).…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin I2 Analogs Inhibit Proinflammatory Cytokine Production and T Cell Stimulatory Function of Dendritic Cells

Zhou

Hashimoto

Goleniewska

et al. 2007

The Journal of Immunology

153

145

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Signaling through the PGI2 receptor (IP) has been shown to inhibit inflammatory responses in mouse models of respiratory syncytial viral infection and OVA-induced allergic responses. However, little is known about the cell types that mediate the anti-inflammatory function of PGI2. In this study, we determined that PGI2 analogs modulate dendritic cell (DC) cytokine production, maturation, and function. We report that PGI2 analogs (iloprost, cicaprost, treprostinil) differentially modulate the response of murine bone marrow-derived DC (BMDC) to LPS in an IP-dependent manner. The PGI2 analogs decreased BMDC production of proinflammatory cytokines (IL-12, TNF-α, IL-1α, IL-6) and chemokines (MIP-1α, MCP-1) and increased the production of the anti-inflammatory cytokine IL-10 by BMDCs. The modulatory effect was associated with IP-dependent up-regulation of intracellular cAMP and down-regulation of NF-κB activity. Iloprost and cicaprost also suppressed LPS-induced expression of CD86, CD40, and MHC class II molecules by BMDCs and inhibited the ability of BMDCs to stimulate Ag-specific CD4 T cell proliferation and production of IL-5 and IL-13. These findings suggest that PGI2 signaling through the IP may exert anti-inflammatory effects by acting on DC.

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Section: Discussionmentioning

confidence: 99%

Prostaglandin I2 Analogs Inhibit Proinflammatory Cytokine Production and T Cell Stimulatory Function of Dendritic Cells

Zhou

Hashimoto

Goleniewska

et al. 2007

The Journal of Immunology

153

145

View full text Add to dashboard Cite

show abstract

“…In this context, both TGF-␤ and IL-10 have been shown to regulate mucosal inflammation (3). In addition, PGI 2 generated during allergic pulmonary inflammation serves to selectively limit the progression of Th2, but not Th1, responses (4).…”

Section: Discussionmentioning

confidence: 99%

“…To examine cytokine production, 8-day polarized cells (5 ϫ 10 5 /ml) were stimulated with immobilized anti-CD3 (2 g/ml) for 24 h, and the supernatants were harvested for measurement of IL-4, IL-5, IL-13, and IFN-␥ by ELISA as described previously (4,22). For IL-10 measurement by ELISA, JES5-2A5 (BD PharMingen) was used as capture Ab and biotinylated polyclonal anti-IL-10 Ab for detection (PeproTech, Rocky Hill, NJ).…”

Section: Measurement Of Cytokine Production By Th2-polarized Cellsmentioning

confidence: 99%

“…Real-time PCR was performed using the Perkin-Elmer AB1 Prism 7700 Sequence Detection System (Applied Biosystems). The expression of GAPDH (housekeeping gene), IL-4, IL-5, IL-10, IL-13, and IFN-␥ was determined (4,23). Equal amounts of cDNA were used in triplicate and amplified with the TaqMan master mix according to manufacturer's instructions (Applied Biosystems).…”

Section: Real-time Rt-pcrmentioning

confidence: 99%

“…However, the specific events that serve to down-regulate airway Th2-mediated inflammation are poorly understood. Certainly, the production of antiinflammatory cytokines TGF-␤ or IL-10 and specific prostanoids at sites of inflammation serve to limit mucosal immune responses (3,4). More notably, regulatory T cells producing high levels of IL-10 have recently been shown to modulate allergen-induced airway responses (5).…”

mentioning

confidence: 99%

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CD4+CD25+ T Cells Regulate Airway Eosinophilic Inflammation by Modulating the Th2 Cell Phenotype

Jaffar

Sivakuru

Roberts

2004

The Journal of Immunology

Self Cite

111

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We used a TCR-transgenic mouse to investigate whether Th2-mediated airway inflammation is influenced by Ag-specific CD4+CD25+ regulatory T cells. CD4+CD25+ T cells from DO11.10 mice expressed the transgenic TCR and mediated regulatory activity. Unexpectedly, depletion of CD4+CD25+ T cells before Th2 differentiation markedly reduced the expression of IL-4, IL-5, and IL-13 mRNA and protein when compared with unfractionated (total) CD4+ Th2 cells. The CD4+CD25−-derived Th2 cells also expressed decreased levels of IL-10 but were clearly Th2 polarized since they did not produce any IFN-γ. Paradoxically, adoptive transfer of CD4+CD25−-derived Th2 cells into BALB/c mice induced an elevated airway eosinophilic inflammation in response to OVA inhalation compared with recipients of total CD4+ Th2 cells. The pronounced eosinophilia was associated with reduced levels of IL-10 and increased amounts of eotaxin in the bronchoalveolar lavage fluid. This Th2 phenotype characterized by reduced Th2 cytokine expression appeared to remain stable in vivo, even after repeated exposure of the animals to OVA aerosols. Our results demonstrate that the immunoregulatory properties of CD4+CD25+ T cells do extend to Th2 responses. Specifically, CD4+CD25+ T cells play a key role in modulating Th2-mediated pulmonary inflammation by suppressing the development of a Th2 phenotype that is highly effective in vivo at promoting airway eosinophilia. Conceivably, this is partly a consequence of regulatory T cells facilitating the production of IL-10.

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Antigen‐specific Treg regulate Th17‐mediated lung neutrophilic inflammation, B‐cell recruitment and polymeric IgA and IgM levels in the airways

et al. 2009

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Th17 cells play key roles in mediating autoimmunity, inflammation and mucosal host defense against pathogens. To determine whether naturally occurring Treg (nTreg) limit Th17-mediated pulmonary inflammation, OVA-specific CD4 1 Th17 cells and expanded CD4 1 CD25 1 Foxp3 1 nTreg were cotransferred into BALB/c mice that were then exposed to OVA aerosols. Th17 cells, when transferred alone, accumulated in the lungs and posterior mediastinal LN and evoked a pronounced airway hyperreactivity and neutrophilic inflammation, characterized by B-cell recruitment and elevated IgA and IgM levels. Cotransfer of antigen-specific nTreg markedly reduced the Th17-induced pulmonary inflammation and associated neutrophilia, B-cell influx and polymeric Ig levels in the airways, but did not inhibit airway hyperreactivity. Moreover, the regulation appeared restricted to the site of mucosal inflammation, since transfer of nTreg did not affect the Th17 response developing in the lung draining LN, as evidenced by unaltered levels of IL-17 production and low numbers of Foxp3 1 Treg. Our findings suggest a crucial role for Th17 cells in mediating airway B-cell influx and IgA response, and demonstrate that antigen-specific nTreg suppress Th17-mediated lung inflammation. These results provide new insights into how Th17 responses are limited and may facilitate development of novel approaches for controlling Th17-induced inflammation.Key words: B cells . Lung inflammation . Regulation . Treg . Th17 cells Supporting Information available online IntroductionEffector CD4 1 T cells, typically, are characterized as Th1, Th2 and Th17 on the basis of their cytokine profiles. Th1 cells secrete IFN-g and are essential for controlling intracellular pathogens, whereas Th2 cells, which produce IL-4, IL-5 and IL-13, clear helminth infections and orchestrate the inflammatory response in asthma. CD4 1 Th17 cells, which are characterized by their secretion of a distinctive set of effector cytokines including IL-17, IL-17F, IL-21 and IL-22, mediate autoimmunity, inflammation and play a crucial role in mucosal host defense against a diverse range of pathogens [1,2]. Th17 cell differentiation in mice not only requires the inductive cytokines TGF-b and IL-6, but also IL-23 for maturation. Moreover, the differentiation of CD4 1 Foxp3 1 Treg and Th17 cells by TGF-b appears to be reciprocally related, since TGF-b alone promotes expression of the transcription factor Foxp3, whereas the combination of IL-6 and TGF-b suppresses Foxp3 expression and enhances IL-17 production [3]. Other cytokines such as IFN-g and IL-4 have been suggested to SHORT COMMUNICATION Ã These authors contributed equally to this work. [8][9][10]. Although both nTreg and iTreg require IL-2 and TGF-b for their maintenance, the two subsets display different modes of generation and costimulatory requirements [10]. Importantly, the stability of their suppressive function in the presence of IL-6 or IL-4 differs, since nTreg are converted to IL-17-producing (Th17) cells in the presence of , while the ...

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A Key Role for Prostaglandin I2 in Limiting Lung Mucosal Th2, But Not Th1, Responses to Inhaled Allergen

Cited by 72 publications

References 41 publications

Prostaglandin I2 Analogs Inhibit Proinflammatory Cytokine Production and T Cell Stimulatory Function of Dendritic Cells

Prostaglandin I2 Analogs Inhibit Proinflammatory Cytokine Production and T Cell Stimulatory Function of Dendritic Cells

CD4+CD25+ T Cells Regulate Airway Eosinophilic Inflammation by Modulating the Th2 Cell Phenotype

Antigen‐specific Treg regulate Th17‐mediated lung neutrophilic inflammation, B‐cell recruitment and polymeric IgA and IgM levels in the airways

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