Yusuke Niwa

IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation.

BACKGROUND IL-22 functions as both a proinflammatory cytokine and an anti-inflammatory cytokine in various inflammations, depending on the cellular and cytokine milieu. However, the roles of IL-22 in the regulation of allergic airway inflammation are still largely unknown. OBJECTIVE We sought to determine whether IL-22 is involved in the regulation of allergic airway inflammation. METHODS We examined IL-22 production and its cellular source at the site of antigen-induced airway inflammation in mice. We also examined the effect of IL-22 neutralization, as well as IL-22 administration, on antigen-induced airway inflammation. We finally examined the effect of IL-22 on IL-25 production from a lung epithelial cell line (MLE-15 cells). RESULTS Antigen inhalation induced IL-22 production in the airways of sensitized mice. CD4(+) T cells, but not other lymphocytes or innate cells, infiltrating in the airways produced IL-22, and one third of IL-22-producing CD4(+) T cells also produced IL-17A. The neutralization of IL-22 by anti-IL-22 antibody enhanced antigen-induced IL-13 production, eosinophil recruitment, and goblet cell hyperplasia in the airways. On the other hand, intranasal administration of recombinant IL-22 attenuated antigen-induced eosinophil recruitment into the airways. Moreover, anti-IL-22 antibody enhanced antigen-induced IL-25 production in the airways, and anti-IL-25 antibody reversed the enhancing effect of anti-IL-22 antibody on antigen-induced eosinophil recruitment into the airways. Finally, IL-22 inhibited IL-13-mediated enhancement of IL-25 expression in IL-1β- or LPS-stimulated MLE-15 cells. CONCLUSION IL-22 attenuates antigen-induced airway inflammation, possibly by inhibiting IL-25 production by lung epithelial cells.

Two Different Transcription Factors Discriminate the −315C>T Polymorphism of the FcεRIα Gene: Binding of Sp1 to −315C and of a High Mobility Group-Related Molecule to −315T

The α-chain is a specific component of FcεRI, which is essential for the cell surface expression of FcεRI and the binding of IgE. Recently, two single nucleotide polymorphisms (SNPs) in the α-chain promoter, −315C>T and −66T>C, have been shown by statistic studies to associate with allergic diseases. The effect of −66 SNP on GATA-1-mediated promoter activity has been already indicated. In the present study, to investigate roles of the −315 SNP on the α-chain promoter functions, the transcription activity was evaluated by reporter assay. The α-chain promoter carrying −315T (minor allele) possessed significantly higher transcriptional activity than that of −315C (major allele). EMSA indicated that the transcription factor Sp1, but not Myc-associated zinc finger protein (MAZ), was bound to the −315C allele probe and that a transcription factor belonging to a high mobility group-family bound to the −315T allele probe. The chromatin immunoprecipitation assay suggested that high mobility group 1, 2, and Sp1 bound around −315 of FcεRIα genomic DNA in vivo in the human basophil cell line KU812 with −315C/T and in human peripheral blood basophils with −315C/C, respectively. When cell surface expression level of FcεRI on basophils was analyzed by flow cytometry, basophils from individuals carrying −315T allele expressed significantly higher amount of FcεRI compared with those of −315C/C. The findings demonstrate that a −315 SNP significantly affects human FcεRI α-chain promoter activity and expression level of FcεRI on basophils by binding different transcription factors to the SNP site.

Granulocyte and monocyte adsorption apheresis for generalized pustular psoriasis

Granulocyte and monocyte adsorption apheresis (GCAP) is an extracorporeal circulation therapy that removes activated granulocytes and monocytes. GCAP was initially approved for the treatment of ulcerative colitis, which is attributed to activated granulocytes and macrophages that infiltrate the target tissues. Generalized pustular psoriasis (GPP) is also supposed to be caused by activated neutrophils. In this study, we treated two patients with refractory GPP by using GCAP. Patient 1, a 68‐year‐old woman who had liver cirrhosis, underwent seven GCAP sessions. Patient 2, a 26‐year‐old woman who had systemic lupus erythematosus and had been treated with systemic corticosteroids, underwent eight GCAP sessions. In both patients, GCAP resulted in an immediate improvement in skin lesions and fever reduction, without any adverse effects. We suggest that GCAP is an effective therapy for refractory GPP.

Efficacy of 308‐nm excimer light for Japanese patients with psoriasis

Ultraviolet irradiation therapy, including psoralen and ultraviolet A therapy and narrow‐band ultraviolet B (310–312 nm) therapy, is a widely used and highly efficient treatment modality for psoriasis. Therapy with 308‐nm excimer light has been reported to be effective for the treatment of psoriasis vulgaris. To evaluate the efficacy of 308‐nm excimer light therapy for Japanese psoriasis patients, seven patients (six men and one woman) with plaque‐type psoriasis were treated with 308‐nm excimer light at 7–14‐day intervals. The Psoriasis Severity Index (PSI) was calculated for individual plaques in order to assess the effectiveness of the therapy. A 74.9% mean improvement in the PSI was observed after 10 treatment sessions. These results suggested that targeted irradiation with 308‐nm excimer light leads to rapid and selective improvement in plaque‐type psoriatic lesions without unnecessary radiation exposure to the surrounding unaffected skin.

Opposite effects of PU.1 on mast cell stimulation

An Ets-family transcription factor PU.1 is involved in the development and specific gene regulation of hematopoietic cells. PU.1 also determines the commitment between several lineages via its expression level. Although enforced expression of PU.1 in mast cells (MC) induced expression of monocyte-specific markers and morphological change from MC to monocytes, especially dendritic cells (DC), in the previous report, intracellular events caused by PU.1 are largely unknown. In the present study, effect of PU.1 on IgE- and LPS-mediated stimulation degrees was analyzed. The amounts of IL-6, IL-13, and TNF-alpha produced from LPS-stimulated MC were markedly increased by overexpression of PU.1. In contrast, IL-6 and IL-13 production levels in response to IgE were reduced by PU.1, whereas that of TNF-alpha was up-regulated. beta-Hexosaminidase release as a means of degranulation was decreased in PU.1 transfectants. When eicosanoid generation in response to IgE-stimulation was analyzed, overexpression of PU.1 reduced leukotriene C(4) (LTC(4)) release, but enhanced PGD(2) production. Microarray analysis suggested that expression of FcepsilonRI signal pathway related molecules were suppressed in PU.1 overexpressing MC as well as DC. These observations indicate that up-regulation of PU.1 suppresses expression of FcepsilonRI signal transduction-related intracellular molecules, but increases the potential of transcription activity of monocyte characters.

Acne conglobata successfully treated by fractional laser after CO2 laser abrasion of cysts combined with topical tretinoin

Dear Editor, Acne conglobata is characterized by the presence of nodulocystic lesions. Conservative therapy with oral and topical antibiotics is usually ineffective. On the other hand, surgical excision is difficult for facial lesions. We applied a CO2 laser to open cysts, fistulas and abscesses, and drained the acne conglobata sinuses, as previously reported. Although discharge of malodorous pus ceased after the CO2 laser treatment, numerous concave scars persisted. Therefore, we additionally treated the patient with a fractional laser. A 21-year-old man presented with severe acne lesions on his face which he had suffered with since his teens. Physical examination revealed a number of nodulocystic lesions with underlying draining abscesses and sinus tracts (Fig. 1a). The lesions had increased in both size and number despite various treatments. He was diagnosed as having acne conglobata. We applied short-pulsed CO2 laser therapy (Lumenis Laser 30C; Nihon Lumenis, Tokyo, Japan) for ablation of the cysts. Under local anesthesia with lidocaine, the cysts were opened along their major axes, and the contents such as keratin and pus were removed. Then, the covering cyst wall was ablated by vaporization using the laser at a power setting of 3 W in continuous wave mode to expose the floor epithelium (Fig. 1b). The treatment was repeated once every 2 weeks. At the same time, the patient started be treated with topical 0.1% tretinoin cream once a day to prevent the appearance of new acne lesions. At 3 months after the start of this laser treatment, the number of cystic lesions had decreased markedly. However, numerous concave scars remained (Fig. 1c). Thus, we additionally applied a fractional laser (Reliant Fraxel SR Laser, Reliant Technologies, Palo Alto, CA, USA), which delivers multiple microscopic laser beams under computerized control. Under local anesthesia with 10% lidocaine cream, one treatment consisted of six passes to attain a final microscopic injury with a density of 1500/cm. The fluency was set to 16 mJ. The treatment was repeated up to seven times at intervals of 4 weeks. At follow up after 6 months without treatment, good cosmetic results were noted and there were no recurrences (Fig. 1d,e). This clinical study was conducted with informed consent from the patient. The symptoms of acne conglobata, such as inflammation and malodorous discharge, do not resolve without removal of the lesions. However, there are no indications for surgical excision of larger facial cysts, because they usually require skin grafting. Thus, we vaporized the covering cyst wall using a CO2 laser, to expose the floor epithelium. Moreover, we also treated the patient with topical tretinoin, not only to prevent increasing in the number of acne lesions but also to reduce the risk of pigmentation and scarring. As a result, the sinuses disappeared with persistence of concave scarring. Although the patient was satisfied with disappearance of the malodorous discharge, we treated the scars with a fractional laser, which was reported to be effective for acne scars, in an effort to elevate the concave scars. It is thought that fractional laser induces remodeling of upper dermis around the microscopic epidermal defects in scars. The combination of a CO2 laser and fractional laser was found to produce clinical improvement in