The effect of substance P on nitric oxide release in a rheumatoid arthritis model.
OBJECTIVE
The inflammatory mediator substance P (SP) acts principally through the neurokinin (NK1) receptor. We assessed the influence of SP on production of NO and its possible role in the pathogenesis of rheumatoid arthritis (RA).


METHODS
The effect of SP (0.1-100 nM) on concentrations of the NO metabolite, nitrite, produced by synovial fibroblasts from RA patients was studied. For comparison, the effects of TNF-alpha (0.57 pM-5.7 nM) and IL-1beta (0.57 pM-5.7 nM) were also studied. In parallel studies, footpad inflammation was induced in NK1 receptor knock-out (KO) and wild-type (WT) mice, and swelling and NO metabolite levels were measured.


RESULTS
In cultured synoviocytes, SP, TNF-alpha and IL-1beta induced significantly increased nitrite concentrations. Consistent with a role for NO in SP-mediated inflammatory reactions, the plasma NO metabolite level in WT mice was significantly increased at 3 days following an injection of 10 mg/ml Mycobacterium tuberculosis, but there was no significant change in NK1 KO mice. These results were paralleled by the changes in footpad swelling in WT mice compared to NK1 KO mice.


CONCLUSIONS
SP, like TNF-alpha and IL-1beta, induces NO in both rheumatoid synoviocytes and experimental models of inflammation. Treatments directed against SP may have important and hitherto unrecognised anti-inflammatory effects.
O'Shaughnessy
M C
MC
Bone and Joint Research Unit, Barts and the London, Queen Mary's School of Medicine and Dentistry, London, EC1M 6BQ, UK.
Vetsika
E-K
EK
Inglis
J J
JJ
Carleson
J
J
Haigh
R
R
Kidd
B L
BL
Winyard
P G
PG
D000368:Aged; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism; D013373:Substance P / Q000502:physiology*; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D053583:Interleukin-1beta; D018377:Neurotransmitter Agents; D009566:Nitrates; D009573:Nitrites; D018040:Receptors, Neurokinin-1; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D013373:Substance P