Nerve growth factor release by human synovial fibroblasts prior to and following exposure to tumor necrosis factor-alpha, interleukin-1 beta and cholecystokinin-8: the possible role of NGF in the inflammatory response.
OBJECTIVE
Aim of this study was to investigate the synthesis, release and effects of nerve growth factor (NGF) in human synovial cells isolated from synovial tissue specimen from healthy and osteoarthritis (OA) patients.


METHODS
Human synovial fibroblasts cultures were established starting from healthy and osteoarthritis patients. NGF protein levels in the culture medium, NGFmRNA and high-affinity NGF receptor (Tyrosine kinase A: TrkA) expression in the cells were evaluated in basal conditions and after stimulation with pro-inflammatory cytokines or with the neuropeptide cholecystokinin-8 (CCK-8). The effect of NGF supplement to culture medium on cell proliferation, TrkA expression, and tumour necrosis factor-alpha (TNF-alpha) and inducible-nitric oxide synthase (iNOS) production was investigated.


RESULTS
Under basal conditions human synovial cells produce and release NGF. Both interleukin-1-beta (IL-1 beta) and TNF-alpha, but not CCK-8 promote NGF synthesis and release from OA cells. TrkA NGF receptors are also expressed in both normal and OA synovial cells. NGF, but not IL-1 beta, TNF-alpha and CCK-8, enhances the expression of TrkA in isolated synovial cells. NGF down-regulates IL-1 beta-induced TNF-alpha and iNOS production by OA synovial fibroblasts.


CONCLUSIONS
NGF is produced and released and TrkA receptors are expressed in synovial inflammation. Overexpression of NGF in inflammed joints might be involved in the modulation rather than in the induction of the joint inflammatory response.
Manni
L
L
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Lundeberg
T
T
Fiorito
S
S
Bonini
S
S
Vigneti
E
E
Aloe
L
L
D002478:Cells, Cultured; D002766:Cholecystokinin / Q000494:pharmacology*; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D007375:Interleukin-1 / Q000494:pharmacology*; D020932:Nerve Growth Factor / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D010003:Osteoarthritis / Q000503:physiopathology*; D010446:Peptide Fragments / Q000494:pharmacology*; D020800:Receptor, Nerve Growth Factor / Q000032:analysis; D013583:Synovial Membrane / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007375:Interleukin-1; D010446:Peptide Fragments; D020800:Receptor, Nerve Growth Factor; D014409:Tumor Necrosis Factor-alpha; C410885:cholecystokinin 8; D002766:Cholecystokinin; D020932:Nerve Growth Factor; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II