Substance P induces tumor necrosis factor-alpha 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)-alpha and histamine from human skin slices in response to substance P and antigen. Substance P induced the release of histamine and TNF-alpha in a dose-dependent manner at concentrations from 0.8 to 100 microM. PD 098059 (2'-amino-3'-methoxyflavone) selectively inhibited the release of TNF-alpha, but not the release of histamine induced by either substance P or antigen. SB 203580 ([4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-++ +imida zole]) slightly inhibited TNF-alpha release induced by antigen, but not that induced by substance P, and slightly enhanced histamine release induced by either stimulation. The release of TNF-alpha in response to either stimulation was inhibited by 1 nM-1 microM dexamethasone, but histamine release was not affected. These results suggest that substance P, in addition to antigen, induced TNF-alpha 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.
Okabe
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Department of Dermatology, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minamiku, 734-8551, Hiroshima, Japan. tokabe@hiroshima-u.ac.jp
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Koro
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Yamamoto
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D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D013373:Substance P / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000378:metabolism
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D013373:Substance P; D003907:Dexamethasone; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one