A novel activity for substance P: stimulation of peroxisome proliferator‐activated receptor‐γ protein expression in human monocytes and macrophages

Abstract

Background and purpose: Substance P (SP) and peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) 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‐γ protein expression in monocytes and macrophages (MDMs: monocyte‐derived macrophages) from healthy smokers and non‐smokers. Experimental approach: PPAR‐γ protein was detected by western blot and quantified by calculating the ratio between PPAR‐γ and β‐actin protein expression. Constitutive tachykinin NK₁ receptor expression in monocytes and MDMs from healthy smokers and non‐smokers was evaluated by western blot. Cytokine release was evaluated by ELISA. Key results: In the concentration range 10⁻¹⁰–10⁻⁶ M, SP stimulated PPAR‐γ 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 NK₁ receptors. SP‐induced expression of the PPAR‐γ protein was receptor‐mediated, as it was reproduced by the NK₁ selective agonist [Sar⁹Met(O₂)¹¹]SP and reversed by the competitive NK₁ antagonist GR71251. SP‐induced maximal effects were similar to those evoked by 15‐deoxy‐Δ^12,14‐prostaglandin J₂; an endogenous PPAR‐γ agonist, and were significantly reduced by a PPAR‐γ antagonist. NK₁ and PPAR‐γ agonists exerted opposite effects on TNF‐α release from monocytes and MDMs. Conclusions and implications: Enhancement of PPAR‐γ protein expression represents a novel activity for SP, which could contribute to a range of chronic inflammatory disorders.