Substance P induces tumor necrosis factor-α release from human skin via mitogen-activated protein kinase
Introduction
Substance P, which is located in cutaneous sensory neurons (Hökfelt et al., 1975), is believed to be a major mediator of neurogenic inflammation (Pernow, 1983). It induces the degranulation of mast cells isolated from human skin (Benyon et al., 1987), releasing chemical mediators such as histamine. Intradermal injection of substance P produces immediate wheal-and-flare responses Hägermark et al., 1978, Jorizzo et al., 1983, Foreman et al., 1983 and granulocyte infiltration in both human (Smith et al., 1993) and animal skin Matsuda et al., 1989, Walsh et al., 1995, Yano et al., 1989. It is therefore accepted that substance P can influence late-phase and/or chronic inflammatory responses by inducing granulocyte infiltration in skin. Using experiments with mast cell-deficient mice, Matsuda et al. (1989) and Yano et al. (1989) have demonstrated that this reaction is mast cell-dependent. Iwamoto et al. (1993) reported that the granulocyte infiltration induced by substance P was inhibited by an antagonist of leukotriene B4, a chemoattractant for granulocytes. We have recently demonstrated the release of leukotriene B4 in correlation with the release of prostaglandin D2 and histamine from guinea pig skin in response to substance P (Furutani et al., 1999). On the other hand, Saban et al. (1997) have shown that substance P-induced migration of neutrophils but not of eosinophils was blocked by a leukotriene inhibitor, and suggested the involvement of tumor necrosis factor (TNF)-α, in addition to leukotriene B4, in the granulocyte infiltration in mouse skin. Various cytokines, including TNF-α, interleukin-4, interleukin-5, interleukin-6, interleukin-8 and interleukin-13, have been reported to be produced by mast cells Gordon and Galli, 1990, Möller et al., 1993, Okayama et al., 1995, Plaut et al., 1989, Toru et al., 1998. Among these cytokines, TNF-α is particularly important in the development of inflammation with leukocyte infiltration. It up-regulates endothelial adhesion molecules, such as endothelial-leukocyte adhesion molecule (ELAM)-1 and vascular cell adhesion molecule (VCAM)-1, which are essential for leukocyte infiltration Walsh et al., 1991, Wellicome et al., 1990. The lack of TNF-α released from mast cells abolished neutrophil infiltration in mice peritonitis evoked by Klebsiella pneumoniae (Malaviya et al., 1996). Moreover, Gordon and Galli (1990) have shown that mast cells are a major source of TNF-α during immunoglobulin (Ig) E-dependent responses. It was also reported that intradermal injection of substance P induced the expression of ELAM-1 on microvascular endothelium (Matis et al., 1990), suggesting the release of TNF-α from skin mast cells in response to substance P. However, it has not been fully investigated whether human skin mast cells release TNF-α in response to substance P. Although Ansel et al. (1993) have shown the expression of messenger RNA (mRNA) and the secretion of TNF-α by murine mast cells in response to substance P, it is widely accepted that characteristics of mast cells vary widely among species and organs Lawrence et al., 1987, Lowman et al., 1988, Bradding et al., 1995. For instance, glucocorticoids inhibit IgE-mediated histamine release from mouse and rat mast cells Daëron et al., 1982, Schleimer et al., 1987, but not from human mast cells (Schleimer et al., 1983). Moreover, the mechanism of signal transduction evoked by substance P is not identical with that evoked by antigen. Furthermore, it has been suggested that mast cells lose some of their functions, such as leukotriene B4 release, when isolated from skin tissues by enzymatic digestion (Levi-Schaffer et al., 1987). In this study, we therefore investigated the release of TNF-α and histamine in response to substance P from human skin slices. To investigate the mechanisms of intracellular signaling for these reactions, we studied the effects of antagonists of mitogen-activated protein (MAP) kinase and dexamethasone on the release of TNF-α and histamine induced by substance P and antigen.
Section snippets
Chemicals
Substance P was purchased from Sigma Aldrich (Tokyo, Japan). House dust mite antigen was obtained from Torii (Tokyo, Japan). PD 098059 (2′-amino-3′-methoxyflavone) was purchased from Research Biochemicals International (Natick, MA). SB 203580 ([4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole]) was kindly donated by SmithKline Beecham (Essex, UK). All other chemicals used in the present study were purchased from Wako (Osaka, Japan).
Skin donors
Normal skin tissue was obtained from 13
Release of histamine from human skin
Substance P induced the release of histamine from sensitized human skin tissue in a dose-dependent manner at all concentrations ranging from 0.8 to 100 μM (Fig. 1A). The histamine release induced by 100 μM substance P, 32.4±8.9% (mean±S.E.M., n=10) was slightly greater than that induced by antigen, 29.5±2.0% (mean±S.E.M., n=10), but the difference was not statistically significant.
Release of TNF-α from human skin
Substance P also induced the release of TNF-α from human skin tissue in a dose-dependent manner at a concentration
Discussion
In spite of evidence suggesting roles for substance P and mast cells in the development of cutaneous inflammation with granulocyte infiltration Matsuda et al., 1989, Smith et al., 1993, Walsh et al., 1995, Yano et al., 1989, the release of cytokines induced from mast cells by substance P and its signal transduction have not been fully investigated. Okayama et al. (1998) have recently reported that substance P induced the release of TNF-α from skin mast cells, which had been enzymatically
Acknowledgements
The generous gift of SB 203580 from SmithKline Beecham (Essex, UK) was greatly appreciated.
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