Effects of Macrolide Antibiotics on Th1 Cell and Th2 Cell Development Mediated by Langerhans Cells

Abstract

-Background:It is well known that Langerhans cells (LCs) work as the primary orchestrators in the polarization of the immune milieu towards a T helper type 1 (Th1) or a Th2 immune response. In this study, we investigated the effects of macrolide antibiotics on Th1 cell and Th2 cell development mediated by LCs. Methods: LC-like dendritic cells (LDCs) were generated from mouse bone marrow cells and used as substitutes for LCs. Mice were primed with ovalbumin (OVA) peptide-pulsed LDCs, which had been treated with each macrolide antibiotic, via the hind footpad. After 5 days, the cytokine response in the popliteal lymph nodes was investigated by enzyme-linked immunosorbent assay. The expression of cell surface molecules on LDCs was investigated using reverse transcriptase polymerase chain reaction. Results: Injection of OVA peptide-pulsed LDCs, which had been treated with josamycin or spiramycin, inhibited Th2 cell development as represented by down-regulation of interleukin (IL)-4 production as well as Th1 cell development as represented by downregulation of interferon (IFN)- production. This inhibition of Th1 cell and Th2 cell development was associated with suppression of CD86 and T-cell immunoglobulin and mucin domain-containing protein (TIM)-4 expression, respectively, in LDCs. Furthermore, Staphylococcus aureus strains isolated from skin lesions of patients with atopic dermatitis (AD) were more susceptible to josamycin than to spiramycin. Conclusions: These results suggest that topical application of josamycin to AD lesions colonized with S. aureus would be beneficial for control of AD by acting on both superficial S. aureus and epidermal LCs, and inhibiting the development of Th2 cells.

Topical Application of Josamycin Inhibits Development of Atopic Dermatitis-Like Skin Lesions in NC/Nga Mice

“…Furthermore, TNCB treatment induced expression of the Th1 cytokine, IFN-γ, in the lymph nodes of NC/Nga mice, and its expression was inhibited by the topical application of josamycin. This might also explain the results of our previous study (12) in which LCs treated with josamycin showed inhibition of not only Th2 cell development but also Th1 cell development in lymph nodes through down-regulation of CD86. On the other hand, elevation of IFN-γ and IL-4 expression in TNCB-treated NC/Nga mice was observed in skin lesions, similarly to human AD lesions (17), and topical application of josamycin inhibited the expression of both IFN-γ and IL-4.…”

“…Furthermore, our previous study showed that S. aureus strains isolated from the lesional skin of AD patients were susceptible to josamycin (12). Since the skin of most AD patients shows superficial S. aureus colonization and barrier disruption due to a decrease of filaggrin (23), bacterial products such as staphylococcal enterotoxins, lipoteichoic acid and peptidoglycan would be expected to penetrate the skin and induce the production of Th2 cells and chemokines, which in turn would induce a Th2 immune response and augment skin inflammation (1,(4)(5)(6)(24)(25)(26).…”

“…The decrease in the number of mast cells was particularly noticeable. Our previous study (12) showed that LCs treated with josamycin inhibited Th2 cell development in lymph nodes through down-regulation of Jagged 1 and T-cell immunoglobulin and mucin domain-containing protein (TIM)-4 expression in LCs. Therefore, it was thought that topical application of josamycin to skin lesions of NC/Nga mice targeted LCs in the epidermis, which then moved to lymph nodes, where Th2 cell development and subsequent IL-4 production were down-regulated.…”

“…Since the skin of most AD patients shows superficial S. aureus colonization and barrier disruption due to a decrease of filaggrin (23), bacterial products such as staphylococcal enterotoxins, lipoteichoic acid and peptidoglycan would be expected to penetrate the skin and induce the production of Th2 cells and chemokines, which in turn would induce a Th2 immune response and augment skin inflammation (1,(4)(5)(6)(24)(25)(26). Therefore, topical application of josamycin to the lesioned skin of AD patients appears to exert an excellent effect involving a bactericidal action against S. aureus and inhibition of the Th2 immune response in lesioned skin by inhibiting the development of LC-mediated allergen-specific Th2 cells, unlike immunosuppressants such as tacrolimus, or steroids (12). Since it is thought that topical application of josamycin to the skin has few side effects, it might be possible to increase its concentration in ointment to a level that would more strongly inhibit Th2 cell development in AD patients and the subsequent Th2 immune response in AD lesions.…”

“…Therefore, allergic inflammation might be controllable through regulation of LCs. In our previous study (12), we found that a macrolide antibiotic, josamycin, had excellent bactericidal activity against S. aureus strains isolated from skin lesions of AD patients and simultaneously inhibited LC-mediated development of Th1 and Th2 cells. These findings suggested that topical application of josamycin to skin lesions of AD patients might be beneficial for control of AD.…”