Substance P induces tumor necrosis factor-α release from human skin via mitogen-activated protein kinase

Substance P plays an important role in neurogenic inflammation with granulocyte infiltration. To investigate cytokines involved in the substance P-induced inflammation and the mechanism of cell activation, we studied the release of TNF (tumor necrosis factor)-α and histamine from human skin slices in response to substance P and antigen. Substance P induced the release of histamine and TNF-α in a dose-dependent manner at concentrations from 0.8 to 100 μM. PD 098059 (2′-amino-3′-methoxyflavone) selectively inhibited the release of TNF-α, but not the release of histamine induced by either substance P or antigen. SB 203580 ([4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1 H-imidazole]) slightly inhibited TNF-α release induced by antigen, but not that induced by substance P, and slightly enhanced histamine release induced by either stimulation. The release of TNF-α in response to either stimulation was inhibited by 1 nM–1 μM dexamethasone, but histamine release was not affected. These results suggest that substance P, in addition to antigen, induced TNF-α release from human skin by a mitogen-activated protein (MAP) kinase, predominantly extracellular signaling-regulated protein kinase (ERK)-dependent, and dexamethasone-sensitive pathway, which is separate from that for histamine release from mast cells.