A novel activity for substance P: stimulation of peroxisome proliferator-activated receptor-gamma protein expression in human monocytes and macrophages.
OBJECTIVE
Substance P (SP) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) play important roles in different inflammatory conditions and are both expressed in human monocytes and macrophages. However, it is not known whether or not they interact. This study was undertaken to evaluate the effects of SP on PPAR-gamma protein expression in monocytes and macrophages (MDMs: monocyte-derived macrophages) from healthy smokers and non-smokers.


METHODS
PPAR-gamma protein was detected by western blot and quantified by calculating the ratio between PPAR-gamma and beta-actin protein expression. Constitutive tachykinin NK(1) receptor expression in monocytes and MDMs from healthy smokers and non-smokers was evaluated by western blot. Cytokine release was evaluated by ELISA.


RESULTS
In the concentration range 10(-10)-10(-6) M, SP stimulated PPAR-gamma protein expression in monocytes and MDMs, being more effective in cells from healthy smokers. Moreover, in these cells there was a constitutively increased expression of NK(1) receptors. SP-induced expression of the PPAR-gamma protein was receptor-mediated, as it was reproduced by the NK(1) selective agonist [Sar(9)Met(O(2))(11)]SP and reversed by the competitive NK(1) antagonist GR71251. SP-induced maximal effects were similar to those evoked by 15-deoxy-Delta(12,14)-prostaglandin J(2); an endogenous PPAR-gamma agonist, and were significantly reduced by a PPAR-gamma antagonist. NK(1) and PPAR-gamma agonists exerted opposite effects on TNF-alpha release from monocytes and MDMs.


CONCLUSIONS
Enhancement of PPAR-gamma protein expression represents a novel activity for SP, which could contribute to a range of chronic inflammatory disorders.
Amoruso
A
A
Department of Medical Sciences, School of Medicine, University of Piemonte Orientale A Avogadro, Novara, Italy.
Bardelli
C
C
Gunella
G
G
Ribichini
F
F
Brunelleschi
S
S
D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D064729:Neurokinin-1 Receptor Antagonists; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D020239:Receptor Cross-Talk / Q000187:drug effects; D018040:Receptors, Neurokinin-1 / Q000819:agonists; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors; D012907:Smoking / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D007202:Indicators and Reagents; D064729:Neurokinin-1 Receptor Antagonists; D047495:PPAR gamma; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D014409:Tumor Necrosis Factor-alpha; C076254:GR 71251; D013373:Substance P