Effects of PGI2 analogues on Th1- and Th2-related chemokines in monocytes via epigenetic regulation

Chang Hung Kuo; Ying Chin Ko; San Nan Yang; Yu Te Chu; Wei Li Wang; Shau Ku Huang; Huan Nan Chen; Wan Ju Wei; Yuh Jyh Jong; Chih Hsing Hung

doi:10.1007/s00109-010-0694-2

Effects of PGI₂ analogues on Th1- and Th2-related chemokines in monocytes via epigenetic regulation

Chang Hung Kuo, Ying Chin Ko, San Nan Yang, Yu Te Chu, Wei Li Wang, Shau Ku Huang, Huan Nan Chen, Wan Ju Wei, Yuh Jyh Jong, Chih Hsing Hung

School of Medicine

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

Chemokines play important roles in asthma. Prostaglandin I₂ (PGI₂) analogue is recently suggested as a candidate for treating asthma. However, the effects of PGI₂ analogues on the expression of Th1- and Th2-related chemokines are unknown. To this end, we investigated the in vitro effects of PGI₂ analogues on the expression of Th1-related chemokine interferon-γ-inducible protein-10 (IP-10/CXCL10) and Th2-related chemokine macrophage-derived chemokine (MDC/CCL22) in human monocytes. The human monocytes were pretreated with iloprost and treprostinil before lipopolysaccharide (LPS) stimulation. IP-10 and MDC were measured by ELISA. Intracellular signaling was investigated by cyclic adenosine monophosphate (cAMP) assay, western blot and chromatin immunoprecipitation. PGI₂ analogues enhanced MDC, but suppressed IP-10 expression in LPS-stimulated monocytes. These effects were reversed by the I prostanoid (IP) receptor antagonist (CAY10449), peroxisomal proliferators-activated receptor (PPAR)-α antagonist (GW6741) and PPAR-γ antagonist (GW9662). PGI₂ analogues increased intracellular cAMP levels. Forskolin, an adenyl cyclase activator, conferred similar effects. PGI₂ analogue-enhanced MDC expression was reduced by nuclear factor (NF) κB inhibitor (BAY 117085) and mitogen-activated protein kinase (MAPK)-p38 inhibitor (SB203580). PGI₂ analogues up-regulated phospho-p65 and phospho-p38 but down-regulated phospho-ERK expression. Iloprost enhanced H3 acetylation in MDC promoter area and suppressed H3 acetylation, H3K4, and H3K36 trimethylation in IP-10 promoter area. PGI₂ analogues enhanced MDC expression via the I prostanoid-receptor-cAMP, PPAR-α and PPAR-γ, NFκB-p65, MAPK-p38-ATF2 pathways and increasing histone acetylation, and suppressed IP-10 expression via the IP-receptor-cAMP, PPAR-γ, MAPK-ERK-ELK1 pathways and inhibiting histone acetylation and trimethylation in LPS-stimulated monocytes. PGI₂ analogues may therefore increase Th2 recruitment and inflammation.

Original language	English (US)
Pages (from-to)	29-41
Number of pages	13
Journal	Journal of Molecular Medicine
Volume	89
Issue number	1
DOIs	https://doi.org/10.1007/s00109-010-0694-2
State	Published - Jan 2011

Keywords

Epigenetics
Interferon-γ-inducible protein-10
Macrophage-derived chemokine
Monocytes
Prostaglandin I

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery
Genetics(clinical)

Access to Document

10.1007/s00109-010-0694-2

Cite this

@article{28e6e5da0cbb4d68b408a8a755c74778,

title = "Effects of PGI2 analogues on Th1- and Th2-related chemokines in monocytes via epigenetic regulation",

abstract = "Chemokines play important roles in asthma. Prostaglandin I2 (PGI2) analogue is recently suggested as a candidate for treating asthma. However, the effects of PGI2 analogues on the expression of Th1- and Th2-related chemokines are unknown. To this end, we investigated the in vitro effects of PGI2 analogues on the expression of Th1-related chemokine interferon-γ-inducible protein-10 (IP-10/CXCL10) and Th2-related chemokine macrophage-derived chemokine (MDC/CCL22) in human monocytes. The human monocytes were pretreated with iloprost and treprostinil before lipopolysaccharide (LPS) stimulation. IP-10 and MDC were measured by ELISA. Intracellular signaling was investigated by cyclic adenosine monophosphate (cAMP) assay, western blot and chromatin immunoprecipitation. PGI2 analogues enhanced MDC, but suppressed IP-10 expression in LPS-stimulated monocytes. These effects were reversed by the I prostanoid (IP) receptor antagonist (CAY10449), peroxisomal proliferators-activated receptor (PPAR)-α antagonist (GW6741) and PPAR-γ antagonist (GW9662). PGI2 analogues increased intracellular cAMP levels. Forskolin, an adenyl cyclase activator, conferred similar effects. PGI2 analogue-enhanced MDC expression was reduced by nuclear factor (NF) κB inhibitor (BAY 117085) and mitogen-activated protein kinase (MAPK)-p38 inhibitor (SB203580). PGI2 analogues up-regulated phospho-p65 and phospho-p38 but down-regulated phospho-ERK expression. Iloprost enhanced H3 acetylation in MDC promoter area and suppressed H3 acetylation, H3K4, and H3K36 trimethylation in IP-10 promoter area. PGI2 analogues enhanced MDC expression via the I prostanoid-receptor-cAMP, PPAR-α and PPAR-γ, NFκB-p65, MAPK-p38-ATF2 pathways and increasing histone acetylation, and suppressed IP-10 expression via the IP-receptor-cAMP, PPAR-γ, MAPK-ERK-ELK1 pathways and inhibiting histone acetylation and trimethylation in LPS-stimulated monocytes. PGI2 analogues may therefore increase Th2 recruitment and inflammation.",

keywords = "Epigenetics, Interferon-γ-inducible protein-10, Macrophage-derived chemokine, Monocytes, Prostaglandin I",

author = "Kuo, {Chang Hung} and Ko, {Ying Chin} and Yang, {San Nan} and Chu, {Yu Te} and Wang, {Wei Li} and Huang, {Shau Ku} and Chen, {Huan Nan} and Wei, {Wan Ju} and Jong, {Yuh Jyh} and Hung, {Chih Hsing}",

note = "Funding Information: Acknowledgements The project is supported by a grant from the Center of Excellence for Environmental Medicine Kaohsiung Medical University Research Foundation KMU-EM-98-4.1and 98-4.2, and Kaohsiung Medical University Hospital Research Foundation KMUH99-9I08.",

year = "2011",

month = jan,

doi = "10.1007/s00109-010-0694-2",

language = "English (US)",

volume = "89",

pages = "29--41",

journal = "Journal of Molecular Medicine",

issn = "0946-2716",

publisher = "Springer Verlag",

number = "1",

}

TY - JOUR

T1 - Effects of PGI2 analogues on Th1- and Th2-related chemokines in monocytes via epigenetic regulation

AU - Kuo, Chang Hung

AU - Ko, Ying Chin

AU - Yang, San Nan

AU - Chu, Yu Te

AU - Wang, Wei Li

AU - Huang, Shau Ku

AU - Chen, Huan Nan

AU - Wei, Wan Ju

AU - Jong, Yuh Jyh

AU - Hung, Chih Hsing

N1 - Funding Information: Acknowledgements The project is supported by a grant from the Center of Excellence for Environmental Medicine Kaohsiung Medical University Research Foundation KMU-EM-98-4.1and 98-4.2, and Kaohsiung Medical University Hospital Research Foundation KMUH99-9I08.

PY - 2011/1

Y1 - 2011/1

N2 - Chemokines play important roles in asthma. Prostaglandin I2 (PGI2) analogue is recently suggested as a candidate for treating asthma. However, the effects of PGI2 analogues on the expression of Th1- and Th2-related chemokines are unknown. To this end, we investigated the in vitro effects of PGI2 analogues on the expression of Th1-related chemokine interferon-γ-inducible protein-10 (IP-10/CXCL10) and Th2-related chemokine macrophage-derived chemokine (MDC/CCL22) in human monocytes. The human monocytes were pretreated with iloprost and treprostinil before lipopolysaccharide (LPS) stimulation. IP-10 and MDC were measured by ELISA. Intracellular signaling was investigated by cyclic adenosine monophosphate (cAMP) assay, western blot and chromatin immunoprecipitation. PGI2 analogues enhanced MDC, but suppressed IP-10 expression in LPS-stimulated monocytes. These effects were reversed by the I prostanoid (IP) receptor antagonist (CAY10449), peroxisomal proliferators-activated receptor (PPAR)-α antagonist (GW6741) and PPAR-γ antagonist (GW9662). PGI2 analogues increased intracellular cAMP levels. Forskolin, an adenyl cyclase activator, conferred similar effects. PGI2 analogue-enhanced MDC expression was reduced by nuclear factor (NF) κB inhibitor (BAY 117085) and mitogen-activated protein kinase (MAPK)-p38 inhibitor (SB203580). PGI2 analogues up-regulated phospho-p65 and phospho-p38 but down-regulated phospho-ERK expression. Iloprost enhanced H3 acetylation in MDC promoter area and suppressed H3 acetylation, H3K4, and H3K36 trimethylation in IP-10 promoter area. PGI2 analogues enhanced MDC expression via the I prostanoid-receptor-cAMP, PPAR-α and PPAR-γ, NFκB-p65, MAPK-p38-ATF2 pathways and increasing histone acetylation, and suppressed IP-10 expression via the IP-receptor-cAMP, PPAR-γ, MAPK-ERK-ELK1 pathways and inhibiting histone acetylation and trimethylation in LPS-stimulated monocytes. PGI2 analogues may therefore increase Th2 recruitment and inflammation.

AB - Chemokines play important roles in asthma. Prostaglandin I2 (PGI2) analogue is recently suggested as a candidate for treating asthma. However, the effects of PGI2 analogues on the expression of Th1- and Th2-related chemokines are unknown. To this end, we investigated the in vitro effects of PGI2 analogues on the expression of Th1-related chemokine interferon-γ-inducible protein-10 (IP-10/CXCL10) and Th2-related chemokine macrophage-derived chemokine (MDC/CCL22) in human monocytes. The human monocytes were pretreated with iloprost and treprostinil before lipopolysaccharide (LPS) stimulation. IP-10 and MDC were measured by ELISA. Intracellular signaling was investigated by cyclic adenosine monophosphate (cAMP) assay, western blot and chromatin immunoprecipitation. PGI2 analogues enhanced MDC, but suppressed IP-10 expression in LPS-stimulated monocytes. These effects were reversed by the I prostanoid (IP) receptor antagonist (CAY10449), peroxisomal proliferators-activated receptor (PPAR)-α antagonist (GW6741) and PPAR-γ antagonist (GW9662). PGI2 analogues increased intracellular cAMP levels. Forskolin, an adenyl cyclase activator, conferred similar effects. PGI2 analogue-enhanced MDC expression was reduced by nuclear factor (NF) κB inhibitor (BAY 117085) and mitogen-activated protein kinase (MAPK)-p38 inhibitor (SB203580). PGI2 analogues up-regulated phospho-p65 and phospho-p38 but down-regulated phospho-ERK expression. Iloprost enhanced H3 acetylation in MDC promoter area and suppressed H3 acetylation, H3K4, and H3K36 trimethylation in IP-10 promoter area. PGI2 analogues enhanced MDC expression via the I prostanoid-receptor-cAMP, PPAR-α and PPAR-γ, NFκB-p65, MAPK-p38-ATF2 pathways and increasing histone acetylation, and suppressed IP-10 expression via the IP-receptor-cAMP, PPAR-γ, MAPK-ERK-ELK1 pathways and inhibiting histone acetylation and trimethylation in LPS-stimulated monocytes. PGI2 analogues may therefore increase Th2 recruitment and inflammation.

KW - Epigenetics

KW - Interferon-γ-inducible protein-10

KW - Macrophage-derived chemokine

KW - Monocytes

KW - Prostaglandin I

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U2 - 10.1007/s00109-010-0694-2

DO - 10.1007/s00109-010-0694-2

M3 - Article

C2 - 21085923

AN - SCOPUS:78651374332

SN - 0946-2716

VL - 89

SP - 29

EP - 41

JO - Journal of Molecular Medicine

JF - Journal of Molecular Medicine

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