No abstract

Substance P (SP) is distributed in both the central and peripheral nervous system. It has various effects on immunocompetent cells, such as macrophages and lymphocytes. The aim of our study was to search for the presence of SP receptors (SP-R) on human cutaneous Langerhans cells (LC), and to determine the effects of SP on LC immunological functions in a model of mixed epidermal cell-lymphocyte reaction (MELR). Radioligand binding studies showed that LC-enriched epidermal cell suspensions reversibly bound SP, and that the specific binding increased with the percentage of LC. Functional assays showed that SP had no effect when added at concentrations from 10(-6) M to 10(-12) M to the MELR. The addition of SP at concentrations of 10(-4) M and 10(-5) M was able to inhibit the allogeneic T-cell response (98.3 +/- 1.8% and 92.8 +/- 8.9% inhibition, respectively) without modifying the cell viability. This inhibition was through an effect of SP on both T-cell and LC function. We conclude that SP has receptors on LC and may inhibit antigen presentation.

Substance P (SP) released by cutaneous C fibres is involved in the physiopathology of cutaneous lesions. As normal human keratinocytes have been reported to express SP receptors, we studied the effects of SP on keratinocyte activation markers such as ICAM-1 induction and cytokine production. Human keratinocytes derived from skin obtained during plastic surgery were cultured in defined medium (MCDB 153) and were stimulated by SP. Flow cytometry analysis showed that SP (10(-7) and 10(-5) M) as well as the specific NK1 agonist Sar9Met(O2)11SP (Sar Met) induced a slight but significant expression of ICAM-1 at the cell surface during treatment periods of 24 h and 48 h. SP (10(-5) M) also induced a significant but transient increase in the production of IL-1alpha, IL-1beta, IL-1 receptor antagonist and IL-8 which was detectable by ELISA techniques 6 h after stimulation. This elevation returned to constitutive levels 24 or 48 h postinduction. TNFalpha secretion was detected in stimulated cells only after 48 h. These results suggest that SP can activate keratinocytes and support its role in the local inflammatory reaction.

Recently, sustance P receptors (SPR) have been detected in neonatal foreskin. Our purpose was to determine the expression of SPR in other localizations than neonatal foreskin. As SP has been implicated in the pathogenesis of inflammatory cutaneous lesions, we wondered whether SPR localization was modified in psoriatic lesions. In normal skin, SP binding sites were detected using biotinylated SP and abrogated by a specific NK1 antagonist (spantide) on blood vessels, sweat glands and hair follicles. In the normal epidermis, SPR were usually observed on granular layers but may also be observed on other cell layers. The SP binding processed on cultured keratinocytes demonstrated that SPR were expressed in the epidermis, except basal cell layers, confirming that keratinocytes constitutively express SPR. In skin lesions of psoriatic patients, SP binding sites were expressed on the uppermost keratinocytes which are not granular cells, and seem to be overexpressed. Our results raise the question of the role of SPR on psoriatic keratinocytes.