p38 MAPK inhibition selectively mitigates inflammatory mediators and VEGF production in AF cells co-cultured with activated macrophage-like THP-1 cells.
OBJECTIVE
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), PGF2alpha, and vascular endothelial growth factor (VEGF). Naïve and macrophage-exposed AF cell responses to 10ng/ml tumor necrosis factor-alpha (TNF-alpha) were compared using the same outcome measures.


RESULTS
IL-6, IL-8, PGE2, PGF2alpha, 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 PGF2alpha production in a dose-dependent manner in co-culture. However, it did not suppress IL-8 and VEGF production. TNF-alpha-stimulated AF cell inflammatory mediators were up-regulated by macrophage exposure. SB202190 successfully suppressed IL-6, IL-8, PGE2, and PGF2alpha secretion in macrophage-exposed AF cells in response to TNF-alpha.


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.
Kim
J H
JH
Department of Neurosurgery, College of Medicine, Korea University, Seoul, South Korea.
Studer
R K
RK
Vo
N V
NV
Sowa
G A
GA
Kang
J D
JD
D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007403:Intervertebral Disc / Q000378:metabolism*; D017116:Low Back Pain / Q000378:metabolism*; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018836:Inflammation Mediators; D015850:Interleukin-6; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases