Effective Treatment of Psoriasis with Narrow-Band UVB Phototherapy Is Linked to Suppression of the IFN and Th17 Pathways
ABSTRACT Narrow-band ultraviolet-B (NB-UVB) phototherapy is an effective treatment for psoriasis. The molecular mechanisms underlying its efficacy are incompletely understood. To identify NB-UVB-induced molecular pathways that may account for its anti-inflammatory efficacy, gene expression profiling was performed using epidermal RNA from lesional and nonlesional skin from patients with psoriasis undergoing NB-UVB therapy. Downregulation of Th17 signaling pathway was observed during NB-UVB therapy in psoriatic epidermis. Strong inhibition of the Th17 pathway by UVB was confirmed in an ex vivo organ culture system by demonstrating reduced signal transducer and activator of transcription 3 (STAT3) phosphorylation and β-defensin-2 production. These results were further substantiated by demonstrating that NB-UVB inhibited the Th17-dependent psoriasis-like dermatitis in mice. Other pathways affected by NB-UVB therapy include the IFN signaling pathway, epidermal differentiation, and other well-known therapeutic targets in psoriasis, such as the glucocorticoid, vitamin D, peroxisome proliferator-activated receptor, and IL-4 signaling pathways. In conclusion, clinical improvement of psoriasis by NB-UVB is linked to suppression of Th17 and type I and type II IFN signaling pathways, which are critical in the pathogenesis of the disease. Our results show that clinically effective NB-UVB therapy is based on suppression of a broad range of important molecular pathways in psoriatic skin.
- SourceAvailable from: Michelle H Nelson
[Show abstract] [Hide abstract]
- "In addition to environmental toxins, it has been reported that exposure to ultraviolet light can also affect the Th17 milieu. Phototherapies using UV light have shown success in the treatment of exacerbating skin diseases such as psoriasis and atopic dermatitis (27, 28). Extensive analysis by Furuhashi et al. revealed that psoriasis patients treated with UV therapy had reduced skin lesions in coordination with decreased levels of Th17 cells. "
ABSTRACT: T helper 17 (Th17) cells play a complex and controversial role in tumor immunity and have been found to exhibit a fluctuating identity within the context of cancer. The recent, expanding literature on these cells attests to their puzzling nature, either promoting or suppressing tumor growth depending on the malignancy and course of therapeutic intervention investigated. This review addresses several newly appreciated factors that may help delineate Th17 cells' immunological properties in the context of cancer. Several reports suggest that inflammatory signals induced in the tumor milieu regulate the functional fate and antitumor activity of Th17 cells. Recent findings also point to significant alterations in Th17 cells due to their interplay with regulatory T lymphocytes and cytotoxic CD8(+) T cells within the tumor microenvironment. Finally, an appreciation for the stem cell-like properties of Th17 cells that augment their persistence and activity emerges from recent reports. The impact of these factors on Th17 cells' antitumor efficacy and how these factors may be exploited to improve cancer therapies will be discussed.Frontiers in Immunology 06/2014; 5:276. DOI:10.3389/fimmu.2014.00276
[Show abstract] [Hide abstract]
- "Strikingly, TCR-mediated stimulation of CD4 + T cells isolated from UV-treated skin induced Irf4 at much lower levels than in T cells from untreated skin, whereas there was relatively little effect on Irf8 (Fig. 5 B). Psoriasis is a Th17-dependent inflammatory disease of the skin that is responsive to treatment with UV (phototherapy; Grundmann-Kollmann et al., 2002; Rácz et al., 2011). Given the finding that UV inhibited TCR-induced Irf4-induction in skin-resident T cells, we asked if the p38 alternative pathway is active in skin-infiltrating T cells in human psoriatic lesions. "
ABSTRACT: Unlike the MAP kinase (MAPK) cascade that phosphorylates p38 on the activation loop, T cell receptor (TCR) signaling results in phosphorylation on Tyr-323 (pY323, alternative pathway). Using mice expressing p38α and p38β with Y323F substitutions, we show that alternatively but not MAPK cascade-activated p38 up-regulates the transcription factors NFATc1 and IRF4, which are required for proliferation and cytokine production. Conversely, activation of p38 with UV or osmotic shock mitigated TCR-mediated activation by phosphorylation and cytoplasmic retention of NFATc1. Notably, UVB treatment of human psoriatic lesions reduced skin-infiltrating p38 pY323(+) T cell IRF4 and IL-17 production. Thus, distinct mechanisms of p38 activation converge on NFATc1 with opposing effects on T cell immunity, which may underlie the beneficial effect of phototherapy on psoriasis.Journal of Experimental Medicine 05/2014; DOI:10.1084/jem.20131917 · 12.52 Impact Factor
[Show abstract] [Hide abstract]
- "In another study, gene expression profiling was performed using epidermal RNA from lesional and nonlesional skin undergoing narrowband UVB. The Th17 pathway was downregulated during narrowband UVB in psoriatic epidermis . In our previous study, photo(chemo)therapy significantly reduced the increased serum levels of both IL-17 and IL-22 in psoriasis patients compared to those in healthy volunteers. "
ABSTRACT: Photo(chemo)therapy is widely used to treat psoriasis, the pathogenesis of which might be caused by an imbalance of Th17 cells/regulatory T cells (Treg). In the present study, we evaluated the effects of photo(chemo)therapy on the Th17/Treg balance and Treg function. Peripheral blood was obtained from psoriasis patients treated with bath-psoralen ultraviolet A (UVA, n = 50) or narrowband ultraviolet B (UVB, n = 18), and age-matched healthy volunteers (n = 20). CD3(+)CD4(+)IL-17A(+) or CD4(+)CD25(+)Foxp3(+)cells were analyzed to estimate Th17 or Treg number by fluorescence-activated cell sorting. Moreover, CD4(+) CD25(-) T cells from patients treated with PUVA(n = 14) were incubated in CFSE and activated with or without CD4(+) CD25(+)T cells, and the suppressive function of CD4(+) CD25(+)T cells were analyzed. Photo(chemo)therapy significantly reduced Th17 levels from 5.66±3.15% to 2.96±2.89% in patients with increased Th17 (Th17/CD4>3.01% [mean+SD of controls]). In contrast, photo(chemo)therapy significantly increased Treg levels from 2.77±0.75 to 3.40±1.88% in patients with less than 4.07% Treg level, defined as the mean of controls. Furthermore, while Treg suppressed the CD4(+)CD25(-) T cell proliferation to a greater extent in controls (Treg Functional Ratio 94.4±4.28%) than in patients (70.3±25.1%), PUVA significantly increased Treg Functional Ratio to 88.1±6.47%. Th17 levels in severe patients (>30 PASI) were significantly higher as compared to controls. Th17 levels that were left after treatment in the patients not achieving PASI 50 (3.78±4.18%) were significantly higher than those in the patients achieving PASI 75 (1.83±1.87%). Treg levels in patients achieving PASI 90 (4.89±1.70%) were significantly higher than those in the patients not achieving PASI 90 (3.90±1.66%). Treg levels prior to treatment with Th17 high decreased group (5.16±2.20%) was significantly higher than that with Th17 high increased group (3.33±1.39%). These findings indicate that Treg is dysfunctional in psoriasis patients, and photochemotherapy restores those dysfunctional Treg. Photo(chemo)therapy resolved the Th17/Treg imbalance in patients with psoriasis.PLoS ONE 01/2013; 8(1):e54895. DOI:10.1371/journal.pone.0054895 · 3.23 Impact Factor