Effects of ultraviolet-inactivated herpes simplex virus type I on atopic dermatitis-like lesions in NC/Nga mice: Role of the suppressor of cytokine signaling in the skin

Abstract

Background: Atopic dermatitis (AD) is characterized by repetitious eczematous skin and is Th2 dominant in nature. Atopic dermatitis lesions have been observed to improve in patients during viral or bacterial infection, such as herpes simplex virus (HSV). A Th1 pathway established to counter viral infection may possibly be the mechanism for the relief of skin lesions in AD. Methods: In animal AD models using NC/Nga mice, the effects of local intra‐ and/or subcutaneous injection of ultraviolet inactivated‐HSV were examined for Th1/Th2 regulation through a negative regulation pathway with suppressor of cytokine signaling (SOCS)‐3 and 5 using immunohistochemistry, in situ hybridization and reverse transcription−polymerase chain reaction. Results: Lesional skin of HSV‐treated mice displayed extensive interleukin (IL)‐12p40‐positive cellular infiltration compared with non‐treated mice and IL‐12p40/signal transducers and activators of transcription (STAT) 4/SOCS5 mRNA expression was noted basically the same in the three groups. Interleukin‐4 receptor‐positive cellular infiltrates in HSV‐treated mice decreased significantly more than in non‐treated mice and IL‐4 mRNA expression in the three groups was essentially the same, but the expression of STAT6 and SOCS3 mRNA specific for the Th2 regulation pathway was reduced more in HSV‐treated compared with non‐treated mice. Expression of SOCS3 mRNA in situ in HSV‐treated epidermis underwent a far greater reduction compared with expression in non‐treated mice. Conclusions: Ultraviolet‐inactivated HSV treatment would appear to induce a Th1 cellular response and downregulate that of the Th2 pathway in AD‐like lesions of NC/Nga mice by bringing about a reduction of SOCS3 expression in the skin. From the present results, certain HSV DNA components may be effective candidates for a new therapeutic approach in refractory AD.

Overexpression of the suppressor of cytokine signalling 3 (SOCS3) in severe atopic dermatitis.

“…Weak SOCS3 expression might thus cause reduction in Th2, resulting in a requirement for involvement of Th1. In our recent report, 11 SOCS3 mRNA expression in lesional skin was reduced more in NC/Nga mice that had been administered ultraviolet‐inactivated herpes simplex virus; their skin lesions improved after virus administration. We believe therefore that SOCS3 reduction downregulates Th2 and thus expression and/or levels of SOCS3 might provide a specific indication of the severity and/or improvement of AD and the shift from Th2 to Th1 or vice versa .…”

“…A recent report indicated that SOCS3 transgenic mice 5 show increased Th2 response. Data from experiments using the AD NC/Nga mouse model 11 clearly indicate strong SOCS3 mRNA expression and Th2 cellular response, with IL‐4‐ and p‐STAT6‐positive cellular infiltrates in the lesional skin of these mice, as has been found in human AD lesions 12 . SOCS3 expression may possibly be specific to atopic disorders and thus serve as an index of their severity 8 .…”

“…A recent report indicated that SOCS3 transgenic mice 5 show increased Th2 response. Data from experiments using the AD NC ⁄ Nga mouse model 11 clearly ; (e) quite strong in situ expression of SOCS3 mRNA in the epidermis and dermal infiltrates of patient 1 (patient with AD; original magnification · 100), which is contrasted with the sense negative control of SOCS3 in situ in the same patient (inset; original magnification · 100). Immunohistochemical antibody sites and mRNA in situ expression were determined with diaminobenzidine solution and counterstaining was carried out lightly with haematoxylin.…”

Much Atopy about the Skin: Genome-Wide Molecular Analysis of Atopic Eczema

“…SOCS3 is a negative signal transducer specific for IL-12 as well as a signal transducer and activator of transcription 4 signaling, and thereby downregulates IFNγ production and Th1 immunity. SOCS3 was later found to be upregulated in an AE-like skin lesion in an AE model NC/Nga mouse [14]. IFNγ and IL-12 production by peripheral blood mononuclear cells increased significantly after successful treatment with topical glucocorticoids, while the production of IL-1, IL-4 and IL-13 was not significantly changed [15].…”

Th1 regulatory events by infectious pathogens, herpes zoster and herpes simplex viruses: prospects for therapeutic options for atopic eczema

“…The authors have experimented with animal models to scientifically support an observed clinical event. We have previously reported an improvement in AD-like lesions by UV-inactivated HSV 1 [55] in a murine atopy model (Nc/Nga mice), supporting a remarkable improvement in eczema lesions at the site of Kaposi's VE. On the other hand, Kawakami et al [56] described a relationship between defective NK cell activity and development of HSV 1-induced severe skin lesions (eczema herpeticum) in eczematous Nc/Nga mice.…”