Increasing attention has been directed towards interactions between components of the nervous system and multiple target cells of the immune system. Communication between nerves and MCs is a prototypic demonstration of such neuroimmune interactions. Several studies have demonstrated that MCs are often found in close contact with nerves and that there may be a functional interaction between mast cells and the nervous system . In addition, recent evidence suggests that SP is an important mediator in intimate nerve-mast cell cross talk . When organ-cultured normal facial skins were exposed to SP uniformly degranulated MCs adjacent the sebaceous glands were observed at the electron microscopic level. Venules around the sebaceous glands of specimens stimulated with SP showed expression of ELAM-1 on the endo-thelia after subsequent culture. Furthermore, preincuba-tion of explants with the SP analogue or with cromolyn sodium, one of the MC inhibitors, abrogated the ability of SP to induce ELAM-1. These findings suggest that SP endogenously released by dermal nerve fibers may be important in the regulation of endothelial-leukocyte interaction via MCs. It has been demonstrated that the proin-flammatory effect of ELAM-1 induction by MC degranulation products is inhibited by blocking antiserum to TNF-a. Thus, SP, contained within dermal nerve fibers, may represent a crucial initial mediator of a cascade of cellular events involving MC degranulation and release of proinflammatory cytokines such as TNF-a, with subsequent induction of adhesion molecules such as E-selectin on adjacent venular endothelia . This would then
Fig. 3. Effects of neuropeptides and NGF on the levels of soluble SCF from cultured human fibroblasts. Cultured medium was collected 72 h after exposure to 100 ng/ml of each substance and then levels of soluble SCF were examined by ELISA. Means were obtained from triplicate cultures of four independent experiments. CGRP = Calcitonin gene-related peptide; VIP = vasoactive intestinal polypeptide; NPY = neuropeptides Y. * p < 0.01 compared with control (unpaired Student's t test).
facilitate the local accumulation of blood leukocytes during the inflammatory response. Immunohistochemical study demonstrated that most of venules around the sebaceous glands not in normal subjects but in acne patients expressed E-selectin (data not shown). We have recently found using immunoelectron-microscopic method that SP is localized within specific granules of human skin MCs . In addition to cutaneous sensory nerves, MC-derived SP may also affect the morphologic and immuno-logic alterations associated with the sebaceous glands and may contribute to the development of the inflammatory events in acne.
The mechanisms of MC hyperplasia around the sebaceous glands in acne patients are unclear. The importance of stem cell factor (SCF), a potent fibroblast-derived MC growth factor, has been demonstrated using MC-deficient mutant mice . SP upregulates the soluble form of SCF by human fibroblasts (fig. 3) in a dose-dependent manner (fig. 4) in monolayer culture, as measured by enzyme-linked immunosorbent assay. Expression of the membrane-bound form of SCF mRNA was detected by reverse transcriptase-PCR in cultured human fibroblasts. A pre-
Fig. 4. A dose-dependent response of soluble SCF from cultured human fibroblasts stimulated with SP. Cultured medium were collected after 48 h exposure to a series of concentration of SP and then levels of soluble SCF were examined by ELISA. Means were obtained from triplicate cultures of four independent experiments. * p < 0.01 compared with medium alone (0) (unpaired Student's t test).
dicted 414-bp cDNA product was produced. When the PCR bands were quantified and the results were expressed as ratios of densitometric scores for SCF and GAPDH for each sample, SCF message after treatment with 102 to 104 ng/ml of SP was relatively more intense than that platelet-derived growth factor, a well-known SCF enhancer  (data not shown). These findings sug gest that SP may be able to enhance MC proliferation through upregulation of SCF secretion and expression by fibroblasts.
On the basis of all the data mentioned above, the following seven findings were found in association with acne inflammation from our in vivo and in vitro studies: (1) Many SP-containing nerve fibers were in close apposition to the sebaceous glands of acne patients (in vivo). (2) SP promoted both the proliferation and the differentiation of the sebaceous glands (in vitro). (3) NEP was expressed in the germinative cells of the sebaceous glands in acne patients (in vivo). SP-induced expression of NEP in sebaceous glands which was localized in the endoplasmic reticulum and the Golgi apparatus (in vitro). (4) There was an increase in the number of nerve fibers around the sebaceous glands in acne patients, which were sometimes invading into the sebaceous glands (in vivo). (5) Immuno-reactivity of NGF was seen in the sebaceous glands only in acne patients (in vivo) and mast cell-derived IL-6 induced expression of sebaceous glands (in vitro). (6) An increase in the number of activated mast cells and a strong expression of E-selectin in postcapillary venules were observed in adjacent areas to the sebaceous glands in acne (in vivo). Mast cell-derived TNF-a induced expression of E-selectin on venules (in vitro). (7) The levels of soluble form of and the expression of membrane-bound form of SCF by fibroblasts were upregulated by SP (in vitro).
Taken together, these findings suggest involvement of neurogenic factors including innervation, NPs, neuropep-tides-degrading enzymes and neurotrophic factors in the inflammatory process of acne and provide new insight into the possible mechanism of exacerbation of acne from the neurological point of view.
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