The analysis on the treatment and the immunological/allergic mechanisms of atopic dermatitis. From the aspect of T cell function (Immunomodulating action by environmental pollutants)

There is growing evidence that diesel exhaust particles (DEP) or folmaldehyde (FA) can induce allergic diseases with increased IgE production and preferential activation of Th2 cells. To clarify the cellular basis of the role of DEP and FA in the induction of Th2-dominant responses, we examined the effects of DEP or FA on the cytokine production by T-cells stimulated with anti-CD3/CD28 antibody and on that by monocyte-derived dendritic cells (MoDCs) stimulated with CD40 ligand and/or IFN-γ. We examined IFN-γ, IL-4, IL-5, IL-8, and IL-10 produced by T-cells and TNF-a, IL-1b, IL-10, and IL-12 produced by MoDCs using real-time PCR analysis or by ELISA. To highlight the effects of DEP or FA, we compared the effects of DEP with those of dexamethasone (DEX) and cyclosporine A(CyA). Both DEP and FA significantly suppressed INF- γ mRNA expression and protein production, while it did not affect IL-4 or IL-5 mRNA expression or protein production. Both DEP and FA suppressed IL-12p40 and IL-12p35 mRNA expression and IL-12p40 production by MoDCs, while it augmented IL-1b mRNA expression. Finally, by using a thiol antioxidant, N-acetylcysteine (NAC), we found that the suppression of INF-g production by DEP- or FA-treated T cells was mediated by oxidative stress. These data revealed a unique characteristic of DEP, namely that they induce a Th2 cytokine milieu in both T cells and DCs. Next, to explore the molecular events underlying the diminished IFN-g and IL-10 production by DEP- or FA-treated T cells, we examined their effects on mRNA expression by T cells stimulated with anti-CD3/anti-CD28 mAb using microarrays and real-time PCR. By real-time PCR, we found that both DEP and FA significantly suppressed mRNA expression of T-bet, Txk and c-Maf but not that of GATA-3, SOCS3, SOCS5, or Gadd45b. The microarrays revealed significant augmentations of two Fox03a-dependent genes, GILZ and Gadd45a, in addition to several other oxidative stress genes, which was confirmed by real-time PCR. Treatment of T cells with N-acetyl cystein, which partially recovered the IFN-g mRNA and protein production, did not restore T-bet or Txk mRNA but suppressed the augmentation of Gadd45a mRNA. These data suggest that both DEP and FA modulate mRNA expression of several transcription factors that play a role in T cell stimulation or Th1/Th2 deviation. Among them, Gadd45a and/or GILZ genes in DEP- or FA-treated T cells may link the stress response with the diminished IFN-g and IL-10 production.