Differential Effects of Corticosteroids and Pimecrolimus on the Developing Skin Immune System in Humans and Mice

Abstract

Atopic dermatitis arises primarily in early infancy. In these patients, corticosteroids are used especially with great caution because of their side effects. Calcineurin inhibitors such as pimecrolimus (PIM) could be useful, but safety concerns have been raised in particular because of the lack of knowledge about their effects on the developing skin immune system. This study was designed to investigate the impact of PIM and corticosteroids on epidermal cells (EC) in infants and newborn mice. We found that the percentage of unfractionated viable infant ECs was significantly decreased in the presence of beta-methasone-17-valerate (BMV) but not PIM. Exposure of unfractionated infant ECs to BMV but not to PIM and vehicle control caused a significant inhibition of the upregulation of CD86 molecules on Langerhans cells (LC). The release of cytokines by LCs and ECs, cultured in the presence of BMV and PIM, was not significantly reduced compared with controls. Topical corticosteroid but not PIM application onto newborn mice induced apoptosis in some LC precursors. Our data suggest that similar to the situation in adult skin, corticosteroids may impair LC maturation as well as viability of ECs in infants, effects not seen with PIM.

Glucocorticosteroids Modify Langerhans Cells To Produce TGF-β and Expand Regulatory T Cells

“…One possible explanation for this discrepancy could be a dosage phenomenon (58), as higher concentrations of GCS within the epidermis upon topical treatment could cause apoptosis, whereas lower amounts of GCS in the epidermis after oral treatment would inhibit the maturation of LCs but not affect their viability. In vitro studies support this theory, as GCSs do not induce apoptosis in LCs in vitro (59), but keep them in an immature stage (60).…”

The Skin as a Route of Allergen Exposure: Part I. Immune Components and Mechanisms

“…Langerhans cells (LCs), identified by the C-type lectin receptor, CD207/ langerin, and Birbeck granules, are present in all layers of the viable epidermis [26•]. The number of epidermal LCs was found to increase or decrease in AD versus healthy epidermis, dependent on disease severity and treatment with topical steroids or calcineurin inhibitors [27]. FcεRI, the high affinity IgE receptor, has been theorized to play a role in antigen-uptake and facilitated antigen presentation by LCs based on observations of higher FcεRI surface expression on LCs in AD skin [28–30].…”

Glucocorticoid receptor translational isoforms underlie maturational stage-specific glucocorticoid sensitivities of dendritic cells in mice and humans

“…However, our findings do agree with the majority of the literature that demonstrates that DCs are sensitive to glucocorticoid killing. 7,9,10,12,15,[18][19][20][21][22][23][24][25] The maturational stage-specific sensitivity of DCs to glucocorticoid-induced apoptosis is thus a novel mechanism underlying the anti-inflammatory and immunosuppressive activities of glucocorticoids. This is the first study that identifies the GR translational isoforms in DCs.…”

“…Although previous studies have examined GR expression in DCs, 9,10,22,25 none of these studies have evaluated the GR translational isoforms. To determine the mechanisms underlying the maturational stage-specific glucocorticoid sensitivity of DCs, we examined the GR isoforms expressed in BMDCs at various stages of maturation using Western blot analysis.…”

“…11,12,15 Consequently, glucocorticoids impair T-cell stimulatory capacity of DCs. 13,14,16,17 In addition, glucocorticoids may reduce the number of DCs via inhibiting DC migration and increasing DC apoptosis, 7,9,10,12,15,[18][19][20][21][22][23][24][25] although some other reports suggest that glucocorticoids do not induce DCs apoptosis. 13,16,26,27 It is not known whether different DC subsets have differential sensitivity to glucocorticoid-induced apoptosis.…”