p38 MAPK inhibition selectively mitigates inflammatory mediators and VEGF production in AF cells co-cultured with activated macrophage-like THP-1 cells

Joo-Han Kim, R. K. Studer, N. V. Vo, G. A. Sowa, J. D. Kang

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Objectives: Recent data have suggested that macrophages are involved in the pathogenesis of discogenic back pain and enhance the secretion of inflammatory mediators in co-cultured annulus fibrosus (AF) cells. The purpose of these studies is to determine the role of p38 mitogen-activated protein kinase (p38 MAPK) signaling in the interactions between macrophage and AF cells. Methods: Human AF cells were co-cultured with phorbol myristate acetate-stimulated macrophage-like THP-1 cells with and without p38 MAPK inhibition. Conditioned media from co-cultured cells were assayed for interleukin (IL)-6, IL-8, prostaglandin E2 (PGE2), PGF2α, and vascular endothelial growth factor (VEGF). Naïve and macrophage-exposed AF cell responses to 10 ng/ml tumor necrosis factor-α (TNF-α) were compared using the same outcome measures. Results: IL-6, IL-8, PGE2, PGF2α, and VEGF were secreted in greater quantities by cells maintained in co-culture compared to macrophages or AF cells cultured alone. SB202190 blunted IL-6, PGE2, and PGF2α production in a dose-dependent manner in co-culture. However, it did not suppress IL-8 and VEGF production. TNF-α-stimulated AF cell inflammatory mediators were up-regulated by macrophage exposure. SB202190 successfully suppressed IL-6, IL-8, PGE2, and PGF2α secretion in macrophage-exposed AF cells in response to TNF-α. Conclusions: Annular injury can result in macrophage infiltration, and this can cause enhanced inflammatory mediator and VEGF production by AF cells. The p38 MAPK pathway signals are responsible for much of IL-6 and PG secretion from AF cells with macrophage-like cells, suggesting that blockade of this signal may serve as a therapeutic approach to discogenic pain.

Original languageEnglish
Pages (from-to)1662-1669
Number of pages8
JournalOsteoarthritis and Cartilage
Volume17
Issue number12
DOIs
Publication statusPublished - 2009 Dec 1

Fingerprint

Macrophages
p38 Mitogen-Activated Protein Kinases
Vascular Endothelial Growth Factor A
Cultured Cells
Proteins
Dinoprost
Interleukin-6
Interleukin-8
Dinoprostone
Tumor Necrosis Factor-alpha
Coculture Techniques
Annulus Fibrosus
Intercellular Signaling Peptides and Proteins
Cell culture
Infiltration
Tetradecanoylphorbol Acetate
Back Pain
Conditioned Culture Medium
Cells
Signal Transduction

Keywords

  • Annulus fibrosus
  • Low back pain
  • Macrophages
  • p38 MAPK
  • SB202190

ASJC Scopus subject areas

  • Biomedical Engineering
  • Orthopedics and Sports Medicine
  • Rheumatology

Cite this

p38 MAPK inhibition selectively mitigates inflammatory mediators and VEGF production in AF cells co-cultured with activated macrophage-like THP-1 cells. / Kim, Joo-Han; Studer, R. K.; Vo, N. V.; Sowa, G. A.; Kang, J. D.

In: Osteoarthritis and Cartilage, Vol. 17, No. 12, 01.12.2009, p. 1662-1669.

Research output: Contribution to journalArticle

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abstract = "Objectives: Recent data have suggested that macrophages are involved in the pathogenesis of discogenic back pain and enhance the secretion of inflammatory mediators in co-cultured annulus fibrosus (AF) cells. The purpose of these studies is to determine the role of p38 mitogen-activated protein kinase (p38 MAPK) signaling in the interactions between macrophage and AF cells. Methods: Human AF cells were co-cultured with phorbol myristate acetate-stimulated macrophage-like THP-1 cells with and without p38 MAPK inhibition. Conditioned media from co-cultured cells were assayed for interleukin (IL)-6, IL-8, prostaglandin E2 (PGE2), PGF2α, and vascular endothelial growth factor (VEGF). Na{\"i}ve and macrophage-exposed AF cell responses to 10 ng/ml tumor necrosis factor-α (TNF-α) were compared using the same outcome measures. Results: IL-6, IL-8, PGE2, PGF2α, and VEGF were secreted in greater quantities by cells maintained in co-culture compared to macrophages or AF cells cultured alone. SB202190 blunted IL-6, PGE2, and PGF2α production in a dose-dependent manner in co-culture. However, it did not suppress IL-8 and VEGF production. TNF-α-stimulated AF cell inflammatory mediators were up-regulated by macrophage exposure. SB202190 successfully suppressed IL-6, IL-8, PGE2, and PGF2α secretion in macrophage-exposed AF cells in response to TNF-α. Conclusions: Annular injury can result in macrophage infiltration, and this can cause enhanced inflammatory mediator and VEGF production by AF cells. The p38 MAPK pathway signals are responsible for much of IL-6 and PG secretion from AF cells with macrophage-like cells, suggesting that blockade of this signal may serve as a therapeutic approach to discogenic pain.",
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T1 - p38 MAPK inhibition selectively mitigates inflammatory mediators and VEGF production in AF cells co-cultured with activated macrophage-like THP-1 cells

AU - Kim, Joo-Han

AU - Studer, R. K.

AU - Vo, N. V.

AU - Sowa, G. A.

AU - Kang, J. D.

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N2 - Objectives: Recent data have suggested that macrophages are involved in the pathogenesis of discogenic back pain and enhance the secretion of inflammatory mediators in co-cultured annulus fibrosus (AF) cells. The purpose of these studies is to determine the role of p38 mitogen-activated protein kinase (p38 MAPK) signaling in the interactions between macrophage and AF cells. Methods: Human AF cells were co-cultured with phorbol myristate acetate-stimulated macrophage-like THP-1 cells with and without p38 MAPK inhibition. Conditioned media from co-cultured cells were assayed for interleukin (IL)-6, IL-8, prostaglandin E2 (PGE2), PGF2α, and vascular endothelial growth factor (VEGF). Naïve and macrophage-exposed AF cell responses to 10 ng/ml tumor necrosis factor-α (TNF-α) were compared using the same outcome measures. Results: IL-6, IL-8, PGE2, PGF2α, and VEGF were secreted in greater quantities by cells maintained in co-culture compared to macrophages or AF cells cultured alone. SB202190 blunted IL-6, PGE2, and PGF2α production in a dose-dependent manner in co-culture. However, it did not suppress IL-8 and VEGF production. TNF-α-stimulated AF cell inflammatory mediators were up-regulated by macrophage exposure. SB202190 successfully suppressed IL-6, IL-8, PGE2, and PGF2α secretion in macrophage-exposed AF cells in response to TNF-α. Conclusions: Annular injury can result in macrophage infiltration, and this can cause enhanced inflammatory mediator and VEGF production by AF cells. The p38 MAPK pathway signals are responsible for much of IL-6 and PG secretion from AF cells with macrophage-like cells, suggesting that blockade of this signal may serve as a therapeutic approach to discogenic pain.

AB - Objectives: Recent data have suggested that macrophages are involved in the pathogenesis of discogenic back pain and enhance the secretion of inflammatory mediators in co-cultured annulus fibrosus (AF) cells. The purpose of these studies is to determine the role of p38 mitogen-activated protein kinase (p38 MAPK) signaling in the interactions between macrophage and AF cells. Methods: Human AF cells were co-cultured with phorbol myristate acetate-stimulated macrophage-like THP-1 cells with and without p38 MAPK inhibition. Conditioned media from co-cultured cells were assayed for interleukin (IL)-6, IL-8, prostaglandin E2 (PGE2), PGF2α, and vascular endothelial growth factor (VEGF). Naïve and macrophage-exposed AF cell responses to 10 ng/ml tumor necrosis factor-α (TNF-α) were compared using the same outcome measures. Results: IL-6, IL-8, PGE2, PGF2α, and VEGF were secreted in greater quantities by cells maintained in co-culture compared to macrophages or AF cells cultured alone. SB202190 blunted IL-6, PGE2, and PGF2α production in a dose-dependent manner in co-culture. However, it did not suppress IL-8 and VEGF production. TNF-α-stimulated AF cell inflammatory mediators were up-regulated by macrophage exposure. SB202190 successfully suppressed IL-6, IL-8, PGE2, and PGF2α secretion in macrophage-exposed AF cells in response to TNF-α. Conclusions: Annular injury can result in macrophage infiltration, and this can cause enhanced inflammatory mediator and VEGF production by AF cells. The p38 MAPK pathway signals are responsible for much of IL-6 and PG secretion from AF cells with macrophage-like cells, suggesting that blockade of this signal may serve as a therapeutic approach to discogenic pain.

KW - Annulus fibrosus

KW - Low back pain

KW - Macrophages

KW - p38 MAPK

KW - SB202190

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