Heme oxygenase 1 attenuates interleukin-1β-induced cytosolic phospholipase A2 expression via a decrease in NADPH oxidase/reactive oxygen species/activator protein 1 activation in rheumatoid arthritis synovial fibroblasts

Pei Ling Chi; Yu Wen Chen; Li Der Hsiao; Yuh Lien Chen; Chuen Mao Yang

doi:10.1002/art.34371

Heme oxygenase 1 attenuates interleukin-1β-induced cytosolic phospholipase A₂ expression via a decrease in NADPH oxidase/reactive oxygen species/activator protein 1 activation in rheumatoid arthritis synovial fibroblasts

Pei Ling Chi, Yu Wen Chen, Li Der Hsiao, Yuh Lien Chen, Chuen Mao Yang^*

^*Corresponding author for this work

School of Nursing

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

36 Scopus citations

Abstract

Objective. Reactive oxygen species (ROS) produced by cytokines induce the expression of inflammatory mediators in rheumatoid arthritis (RA). Heme oxygenase 1 (HO-1) exerts an antiinflammatory effect. The aim of this study was to examine the mechanisms underlying interleukin-1β (IL-1β)-induced cytosolic phospholipase A₂ (cPLA₂) expression through ROS generation as modulated by HO-1 in RA synovial fibroblasts (RASFs). Methods. IL-1β-induced ROS generation was determined by flow cytometry. The involvement of MAPKs and NADPH oxidase (NOX)/ROS in IL-1β-induced cPLA ₂ expression was investigated using pharmacologic inhibitors and transfection with small interfering RNAs (siRNAs) and was analyzed by Western blotting and promoter assay. Overexpression of HO-1 was performed by transfection of RASFs with a recombinant adenovirus containing human HO-1 plasmid. SCID mice with inflammation caused by IL-1β were infected with adenovirus containing HO-1. Histologic characterization of joint inflammation and local expression of cPLA₂ were evaluated after treatment. Results. IL-1β-induced cPLA₂ expression was mediated through NOX activation/ROS production, which was attenuated by N-acetylcysteine (NAC; a scavenger of ROS), the inhibitors of NOX (diphenyleneiodonium chloride and apocynin), MEK-1/2 (U0126), and JNK-1/2 (SP600125), transfection with the respective siRNAs, and the overexpression of HO-1 in RASFs. IL-1β-induced cPLA₂ expression was mediated through recruitment of activator protein 1 (AP-1) to the cPLA₂promoter region, which was attenuated by NAC and overexpression of HO-1. Furthermore, HO-1 overexpression inhibited IL-1β-mediated cPLA₂ expression in SCID mice. Conclusion. In RASFs, IL-1β induced cPLA₂ expression via activation of p42/p44 MAPK and JNK-1/2, leading to p47^phox phosphorylation, ROS production, and AP-1 activation. The induction of HO-1 exerted protective effects on the pathogenesis of RA.

Original language	English
Pages (from-to)	2114-2125
Number of pages	12
Journal	Arthritis and Rheumatism
Volume	64
Issue number	7
DOIs	https://doi.org/10.1002/art.34371
State	Published - 07 2012

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Chi, P. L., Chen, Y. W., Hsiao, L. D., Chen, Y. L., & Yang, C. M. (2012). Heme oxygenase 1 attenuates interleukin-1β-induced cytosolic phospholipase A₂ expression via a decrease in NADPH oxidase/reactive oxygen species/activator protein 1 activation in rheumatoid arthritis synovial fibroblasts. Arthritis and Rheumatism, 64(7), 2114-2125. https://doi.org/10.1002/art.34371

@article{d976a65e3f4249fb87eacacc3abd9965,

title = "Heme oxygenase 1 attenuates interleukin-1β-induced cytosolic phospholipase A2 expression via a decrease in NADPH oxidase/reactive oxygen species/activator protein 1 activation in rheumatoid arthritis synovial fibroblasts",

abstract = "Objective. Reactive oxygen species (ROS) produced by cytokines induce the expression of inflammatory mediators in rheumatoid arthritis (RA). Heme oxygenase 1 (HO-1) exerts an antiinflammatory effect. The aim of this study was to examine the mechanisms underlying interleukin-1β (IL-1β)-induced cytosolic phospholipase A2 (cPLA2) expression through ROS generation as modulated by HO-1 in RA synovial fibroblasts (RASFs). Methods. IL-1β-induced ROS generation was determined by flow cytometry. The involvement of MAPKs and NADPH oxidase (NOX)/ROS in IL-1β-induced cPLA 2 expression was investigated using pharmacologic inhibitors and transfection with small interfering RNAs (siRNAs) and was analyzed by Western blotting and promoter assay. Overexpression of HO-1 was performed by transfection of RASFs with a recombinant adenovirus containing human HO-1 plasmid. SCID mice with inflammation caused by IL-1β were infected with adenovirus containing HO-1. Histologic characterization of joint inflammation and local expression of cPLA2 were evaluated after treatment. Results. IL-1β-induced cPLA2 expression was mediated through NOX activation/ROS production, which was attenuated by N-acetylcysteine (NAC; a scavenger of ROS), the inhibitors of NOX (diphenyleneiodonium chloride and apocynin), MEK-1/2 (U0126), and JNK-1/2 (SP600125), transfection with the respective siRNAs, and the overexpression of HO-1 in RASFs. IL-1β-induced cPLA2 expression was mediated through recruitment of activator protein 1 (AP-1) to the cPLA2promoter region, which was attenuated by NAC and overexpression of HO-1. Furthermore, HO-1 overexpression inhibited IL-1β-mediated cPLA2 expression in SCID mice. Conclusion. In RASFs, IL-1β induced cPLA2 expression via activation of p42/p44 MAPK and JNK-1/2, leading to p47phox phosphorylation, ROS production, and AP-1 activation. The induction of HO-1 exerted protective effects on the pathogenesis of RA.",

author = "Chi, {Pei Ling} and Chen, {Yu Wen} and Hsiao, {Li Der} and Chen, {Yuh Lien} and Yang, {Chuen Mao}",

year = "2012",

month = jul,

doi = "10.1002/art.34371",

language = "英语",

volume = "64",

pages = "2114--2125",

journal = "Arthritis and Rheumatism",

issn = "0004-3591",

publisher = "John Wiley & Sons Inc.",

number = "7",

}

Chi, PL, Chen, YW, Hsiao, LD, Chen, YL & Yang, CM 2012, 'Heme oxygenase 1 attenuates interleukin-1β-induced cytosolic phospholipase A₂ expression via a decrease in NADPH oxidase/reactive oxygen species/activator protein 1 activation in rheumatoid arthritis synovial fibroblasts', Arthritis and Rheumatism, vol. 64, no. 7, pp. 2114-2125. https://doi.org/10.1002/art.34371

Heme oxygenase 1 attenuates interleukin-1β-induced cytosolic phospholipase A₂ expression via a decrease in NADPH oxidase/reactive oxygen species/activator protein 1 activation in rheumatoid arthritis synovial fibroblasts. / Chi, Pei Ling; Chen, Yu Wen; Hsiao, Li Der et al.
In: Arthritis and Rheumatism, Vol. 64, No. 7, 07.2012, p. 2114-2125.

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

TY - JOUR

T1 - Heme oxygenase 1 attenuates interleukin-1β-induced cytosolic phospholipase A2 expression via a decrease in NADPH oxidase/reactive oxygen species/activator protein 1 activation in rheumatoid arthritis synovial fibroblasts

AU - Chi, Pei Ling

AU - Chen, Yu Wen

AU - Hsiao, Li Der

AU - Chen, Yuh Lien

AU - Yang, Chuen Mao

PY - 2012/7

Y1 - 2012/7

N2 - Objective. Reactive oxygen species (ROS) produced by cytokines induce the expression of inflammatory mediators in rheumatoid arthritis (RA). Heme oxygenase 1 (HO-1) exerts an antiinflammatory effect. The aim of this study was to examine the mechanisms underlying interleukin-1β (IL-1β)-induced cytosolic phospholipase A2 (cPLA2) expression through ROS generation as modulated by HO-1 in RA synovial fibroblasts (RASFs). Methods. IL-1β-induced ROS generation was determined by flow cytometry. The involvement of MAPKs and NADPH oxidase (NOX)/ROS in IL-1β-induced cPLA 2 expression was investigated using pharmacologic inhibitors and transfection with small interfering RNAs (siRNAs) and was analyzed by Western blotting and promoter assay. Overexpression of HO-1 was performed by transfection of RASFs with a recombinant adenovirus containing human HO-1 plasmid. SCID mice with inflammation caused by IL-1β were infected with adenovirus containing HO-1. Histologic characterization of joint inflammation and local expression of cPLA2 were evaluated after treatment. Results. IL-1β-induced cPLA2 expression was mediated through NOX activation/ROS production, which was attenuated by N-acetylcysteine (NAC; a scavenger of ROS), the inhibitors of NOX (diphenyleneiodonium chloride and apocynin), MEK-1/2 (U0126), and JNK-1/2 (SP600125), transfection with the respective siRNAs, and the overexpression of HO-1 in RASFs. IL-1β-induced cPLA2 expression was mediated through recruitment of activator protein 1 (AP-1) to the cPLA2promoter region, which was attenuated by NAC and overexpression of HO-1. Furthermore, HO-1 overexpression inhibited IL-1β-mediated cPLA2 expression in SCID mice. Conclusion. In RASFs, IL-1β induced cPLA2 expression via activation of p42/p44 MAPK and JNK-1/2, leading to p47phox phosphorylation, ROS production, and AP-1 activation. The induction of HO-1 exerted protective effects on the pathogenesis of RA.

AB - Objective. Reactive oxygen species (ROS) produced by cytokines induce the expression of inflammatory mediators in rheumatoid arthritis (RA). Heme oxygenase 1 (HO-1) exerts an antiinflammatory effect. The aim of this study was to examine the mechanisms underlying interleukin-1β (IL-1β)-induced cytosolic phospholipase A2 (cPLA2) expression through ROS generation as modulated by HO-1 in RA synovial fibroblasts (RASFs). Methods. IL-1β-induced ROS generation was determined by flow cytometry. The involvement of MAPKs and NADPH oxidase (NOX)/ROS in IL-1β-induced cPLA 2 expression was investigated using pharmacologic inhibitors and transfection with small interfering RNAs (siRNAs) and was analyzed by Western blotting and promoter assay. Overexpression of HO-1 was performed by transfection of RASFs with a recombinant adenovirus containing human HO-1 plasmid. SCID mice with inflammation caused by IL-1β were infected with adenovirus containing HO-1. Histologic characterization of joint inflammation and local expression of cPLA2 were evaluated after treatment. Results. IL-1β-induced cPLA2 expression was mediated through NOX activation/ROS production, which was attenuated by N-acetylcysteine (NAC; a scavenger of ROS), the inhibitors of NOX (diphenyleneiodonium chloride and apocynin), MEK-1/2 (U0126), and JNK-1/2 (SP600125), transfection with the respective siRNAs, and the overexpression of HO-1 in RASFs. IL-1β-induced cPLA2 expression was mediated through recruitment of activator protein 1 (AP-1) to the cPLA2promoter region, which was attenuated by NAC and overexpression of HO-1. Furthermore, HO-1 overexpression inhibited IL-1β-mediated cPLA2 expression in SCID mice. Conclusion. In RASFs, IL-1β induced cPLA2 expression via activation of p42/p44 MAPK and JNK-1/2, leading to p47phox phosphorylation, ROS production, and AP-1 activation. The induction of HO-1 exerted protective effects on the pathogenesis of RA.

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U2 - 10.1002/art.34371

DO - 10.1002/art.34371

M3 - 文章

C2 - 22231145

AN - SCOPUS:84863222142

SN - 0004-3591

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JO - Arthritis and Rheumatism

JF - Arthritis and Rheumatism

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