Stimulation of inducible nitric oxide synthase by monosodium urate crystals in macrophages and expression of iNOS in gouty arthritis

Linda Chen, Ming-Shium Hsieh, Hsin Chiu Ho, Yung Hung Liu, Der Tsay Chou, Shu-Huei Tsai

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

From the studies on the involvement of iNOS in arthritis, it is clear that attention has focused primarily on rheumatoid arthritis (RA) and osteoarthritis (OA). To date, little is known about the role of iNOS in the pathophysiology of gouty arthritis (GA). Here, we investigated the significance of iNOS expression in cell culture system as well as in GA patients. Gouty crystals monosodium urate (MSU) appeared to up-regulate inducible nitric oxide synthase (iNOS) mRNA and protein expression in a concentration- and time-dependent manner in RAW264.7 macrophages. This increase of iNOS expression is attributable to the activation of multiple signaling pathways. Evidence for this was initially established by inhibitor treatment of cells in the presence of MSU. While the JAK inhibitor AG490, the PI3K inhibitor LY294002, and the NFκB inhibitor PDTC abrogated almost completely the expression of iNOS induced by MSU, the ERK1/2 inhibitor PD98059 was only partially effective. Furthermore, the effect of MSU on the activation of PI3K/Akt, JAK/STAT, ERK1/2, and NFκB signaling molecules was carefully examined. Moreover, it was shown that GAS and NFκB motifs are required for iNOS expression mediated by MSU. In addition, synovial tissues obtained from GA patients displayed enhanced expression of iNOS when compared with normal synovium. Taken together, these findings provide the first evidence for the potential importance of iNOS in the pathogenesis of GA as well as RA and OA, and in turn raise the possibility that iNOS may be an ideal target for preventive therapy in human arthritis.

Original languageEnglish
Pages (from-to)228-236
Number of pages9
JournalNitric Oxide - Biology and Chemistry
Volume11
Issue number3
DOIs
Publication statusPublished - Nov 2004

Fingerprint

Gouty Arthritis
Macrophages
Nitric Oxide Synthase Type II
Uric Acid
Crystals
Phosphatidylinositol 3-Kinases
Osteoarthritis
Arthritis
Rheumatoid Arthritis
Chemical activation
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Synovial Membrane
Cell culture
Up-Regulation
Cell Culture Techniques
Cells

Keywords

  • Arthritis
  • Gouty
  • iNOS
  • MSU

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Stimulation of inducible nitric oxide synthase by monosodium urate crystals in macrophages and expression of iNOS in gouty arthritis. / Chen, Linda; Hsieh, Ming-Shium; Ho, Hsin Chiu; Liu, Yung Hung; Chou, Der Tsay; Tsai, Shu-Huei.

In: Nitric Oxide - Biology and Chemistry, Vol. 11, No. 3, 11.2004, p. 228-236.

Research output: Contribution to journalArticle

Chen, Linda ; Hsieh, Ming-Shium ; Ho, Hsin Chiu ; Liu, Yung Hung ; Chou, Der Tsay ; Tsai, Shu-Huei. / Stimulation of inducible nitric oxide synthase by monosodium urate crystals in macrophages and expression of iNOS in gouty arthritis. In: Nitric Oxide - Biology and Chemistry. 2004 ; Vol. 11, No. 3. pp. 228-236.
@article{ac15b25de65f4790ba0226af1cbd3d23,
title = "Stimulation of inducible nitric oxide synthase by monosodium urate crystals in macrophages and expression of iNOS in gouty arthritis",
abstract = "From the studies on the involvement of iNOS in arthritis, it is clear that attention has focused primarily on rheumatoid arthritis (RA) and osteoarthritis (OA). To date, little is known about the role of iNOS in the pathophysiology of gouty arthritis (GA). Here, we investigated the significance of iNOS expression in cell culture system as well as in GA patients. Gouty crystals monosodium urate (MSU) appeared to up-regulate inducible nitric oxide synthase (iNOS) mRNA and protein expression in a concentration- and time-dependent manner in RAW264.7 macrophages. This increase of iNOS expression is attributable to the activation of multiple signaling pathways. Evidence for this was initially established by inhibitor treatment of cells in the presence of MSU. While the JAK inhibitor AG490, the PI3K inhibitor LY294002, and the NFκB inhibitor PDTC abrogated almost completely the expression of iNOS induced by MSU, the ERK1/2 inhibitor PD98059 was only partially effective. Furthermore, the effect of MSU on the activation of PI3K/Akt, JAK/STAT, ERK1/2, and NFκB signaling molecules was carefully examined. Moreover, it was shown that GAS and NFκB motifs are required for iNOS expression mediated by MSU. In addition, synovial tissues obtained from GA patients displayed enhanced expression of iNOS when compared with normal synovium. Taken together, these findings provide the first evidence for the potential importance of iNOS in the pathogenesis of GA as well as RA and OA, and in turn raise the possibility that iNOS may be an ideal target for preventive therapy in human arthritis.",
keywords = "Arthritis, Gouty, iNOS, MSU",
author = "Linda Chen and Ming-Shium Hsieh and Ho, {Hsin Chiu} and Liu, {Yung Hung} and Chou, {Der Tsay} and Shu-Huei Tsai",
year = "2004",
month = "11",
doi = "10.1016/j.niox.2004.09.003",
language = "English",
volume = "11",
pages = "228--236",
journal = "Nitric Oxide - Biology and Chemistry",
issn = "1089-8603",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Stimulation of inducible nitric oxide synthase by monosodium urate crystals in macrophages and expression of iNOS in gouty arthritis

AU - Chen, Linda

AU - Hsieh, Ming-Shium

AU - Ho, Hsin Chiu

AU - Liu, Yung Hung

AU - Chou, Der Tsay

AU - Tsai, Shu-Huei

PY - 2004/11

Y1 - 2004/11

N2 - From the studies on the involvement of iNOS in arthritis, it is clear that attention has focused primarily on rheumatoid arthritis (RA) and osteoarthritis (OA). To date, little is known about the role of iNOS in the pathophysiology of gouty arthritis (GA). Here, we investigated the significance of iNOS expression in cell culture system as well as in GA patients. Gouty crystals monosodium urate (MSU) appeared to up-regulate inducible nitric oxide synthase (iNOS) mRNA and protein expression in a concentration- and time-dependent manner in RAW264.7 macrophages. This increase of iNOS expression is attributable to the activation of multiple signaling pathways. Evidence for this was initially established by inhibitor treatment of cells in the presence of MSU. While the JAK inhibitor AG490, the PI3K inhibitor LY294002, and the NFκB inhibitor PDTC abrogated almost completely the expression of iNOS induced by MSU, the ERK1/2 inhibitor PD98059 was only partially effective. Furthermore, the effect of MSU on the activation of PI3K/Akt, JAK/STAT, ERK1/2, and NFκB signaling molecules was carefully examined. Moreover, it was shown that GAS and NFκB motifs are required for iNOS expression mediated by MSU. In addition, synovial tissues obtained from GA patients displayed enhanced expression of iNOS when compared with normal synovium. Taken together, these findings provide the first evidence for the potential importance of iNOS in the pathogenesis of GA as well as RA and OA, and in turn raise the possibility that iNOS may be an ideal target for preventive therapy in human arthritis.

AB - From the studies on the involvement of iNOS in arthritis, it is clear that attention has focused primarily on rheumatoid arthritis (RA) and osteoarthritis (OA). To date, little is known about the role of iNOS in the pathophysiology of gouty arthritis (GA). Here, we investigated the significance of iNOS expression in cell culture system as well as in GA patients. Gouty crystals monosodium urate (MSU) appeared to up-regulate inducible nitric oxide synthase (iNOS) mRNA and protein expression in a concentration- and time-dependent manner in RAW264.7 macrophages. This increase of iNOS expression is attributable to the activation of multiple signaling pathways. Evidence for this was initially established by inhibitor treatment of cells in the presence of MSU. While the JAK inhibitor AG490, the PI3K inhibitor LY294002, and the NFκB inhibitor PDTC abrogated almost completely the expression of iNOS induced by MSU, the ERK1/2 inhibitor PD98059 was only partially effective. Furthermore, the effect of MSU on the activation of PI3K/Akt, JAK/STAT, ERK1/2, and NFκB signaling molecules was carefully examined. Moreover, it was shown that GAS and NFκB motifs are required for iNOS expression mediated by MSU. In addition, synovial tissues obtained from GA patients displayed enhanced expression of iNOS when compared with normal synovium. Taken together, these findings provide the first evidence for the potential importance of iNOS in the pathogenesis of GA as well as RA and OA, and in turn raise the possibility that iNOS may be an ideal target for preventive therapy in human arthritis.

KW - Arthritis

KW - Gouty

KW - iNOS

KW - MSU

UR - http://www.scopus.com/inward/record.url?scp=9744286978&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=9744286978&partnerID=8YFLogxK

U2 - 10.1016/j.niox.2004.09.003

DO - 10.1016/j.niox.2004.09.003

M3 - Article

VL - 11

SP - 228

EP - 236

JO - Nitric Oxide - Biology and Chemistry

JF - Nitric Oxide - Biology and Chemistry

SN - 1089-8603

IS - 3

ER -