It has been reported that serum IgE levels are elevated in 30-40% of healthy individuals and that the early presence of elevated serum IgE does not predict the development of atopic dermatitis. Furthermore, repeated antigen application on the murine skin results in the manifestations similar to atopic dermatitis and elevation in serum IgE, suggesting that IgE production is secondary to the dermatitis. In this regard, early treatment with local steroid administration would reduce chronic inflammation and thereby inhibit IgE production.

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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.

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It has been accepted that atopic dermatitis is regarded as Atopic Eczema/Dermatitis syndrome on the basis of clinical manifestations and recent advance on the pathomechanisms of atopic dermatitis. These include innate-type atopic dermatitis and acquired-type atopic dermatitis or intrinsic atopic dermatitis and extrinsic atopic dermatitis.
These recognitions are very important to manage the refractory patients with atopic dermatitis. In this review, I would like to summarize the recent findings on cytokine network in atopic dermatitis.

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In spite of the progress in the immunological study of atopic dermatitis (AD), the pathogenesis of this disease still remains unclear. Eosinophil number in the lesional skin and peropheral blood are elevated in most AD patients. Moreover, eosinophil granule proteins are deposited in the AD lesions. These observations suggest a pivotal role of eosinophils in the pathogenesis of AD. Furthermore, AD is associated with increased production of a T helper 2 cytokine, interleukin (IL)-5, which specifically acts on production, activation, and life-prolongation of eosinophils. Based on these observations, eosinophils appear to be interesting targets for therapy in AD.

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Atopic dermatitis (AD) is a recurrent chronic eczematous skin disease. Histoclogically AD shows a large number of T cells, eosinophils and mast cells infiltration into the lesional skin. Recently, chemokines are identified. Specific chemokines attract specific types of leukocytes in the inflammatory sites. TARC/CCL17, MDC/CCL22, CTACK/CCL27 participate in the pathogenesis of AD. High levels of serum CCL17 and CCL27 have been identified in AD patients, in accordance with the strong expression of these molecules in the lesional epidermis of AD patients. Corticosteroids and tacrolimus inhibit these productions in PBMCs of AD patients. TSLP, secreted by epidermal kertatinocytes, induce CCL17 and CCL22 mRNA expression in lesional skin in K14/TSLP transgenic mice. Future therapies targeting chemokines and chemokine receptors will be discussed.

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Unfortunately chemical contamination in environment is considerably serious. Many changes of environmental agent are important in increase of allergic disease of these days, and we hypothesize it is caused by a large quantity of chemical contamination. We take up two chemicals in this paper, one is tributyltin (TBT), another one is formaldehyde (FA) which is causative agent of sick house syndrome. TBT is one of environmental endocrine disrupter, and it let Th1/Th2 balance shift to Th2, it is therefore indicated that TBT contributes to increase of allergic disease. In addition, it is discussed FA is an aggravation factor for atopic dermatitis through a nonallergic mechanism. It is not easy to analyse of environmental factor, but it is thought that it is necessary we pile up new knowledge and continue sounding an alarm bell as environmental issues.

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Staphylococcus colonization is one of the aggravating factors in patients with atopic dermatitis. The Th2 inflammatory response and persistent IL-18 secretion from keratinocytes is induced by wall TA and protein A, respectively. Staphylococcus enterotoxins A (SEA) and B (SEB) stimulate the expression of ICAM-1 and HLA-DR in normal human keratinocytes, and more than half of patients with atopic dermatitis have specific IgE antibodies to SEA and/or SEB in their serum. Epicutaneous sensitization with SEB elicites a local, cutaneous inflammatory response characterized by dermal infiltration with eosinophils and mononuclear cells, and induces mRNA expression of the Th2 cytokine, IL-4 without increased expression of the Th1 cytokine, IFN-γ. Epicutaneous exposure to superantigens skews the immune response toward Th2, leading to allergic skin inflammation and increased IgE synthesis. Patients with atopic dermatitis have significantly increased numbers of regulatory T (Treg) cells with normal immunosuppressive activity. However, after superantigen stimulation, Treg cells lose their immunosuppressive activity. S.aureus, therefore, may aggravate atopic dermatitis by immunomudulatory effects of the cell components and exotoxins. Neither antimicrobial nor antiseptic treatment is effective for eradication of colonizing S.aureus in the horny layers covered with biofilm.

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There are diverse factors which worsen atopic dermatitis(AD), although they vary from person to person. Patients with AD often claim that the sunlight exacerbates their skin conditions. Some of dermatologists also believe that the sunlight may be one of the aggravative factors of AD. However, there are no scientific evidences that can explain the mechanisms by which the sunlight or ultra-violet radiation aggravates eczematous conditions. Photosensitivity disease, such as polymorphous light eruption, chronic actinic dermatitis and photoallergic contact dermatitis, associate with AD in some patients. Pruritus may be increased after sunlight exposure because of increased skin temperature or sweating. These cases are not true photoexacerbation, but pseudo-photosensitivity. In contrast, it is well known that ultraviolet radiation reveals therapeutic effect on AD. A number of modalities of photo (chemo)- therapy are widely used for AD treatment. The action modes of ultraviolet radiation can be understood from the photo-immunological point of view.

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Itch is a major symptom of atopic dermatitis, for which there are no sufficiently effective therapies. Recent studies have shown that sensitization for itch plays a crucial role in pruritus of atopic dermatitis. Several inflammatory mediators and neurotrophic factors have been demonstrated to sensitize peripheral neurons. Moreover, continuous activation of peripheral C-nerves leads to sensitization of secondary afferent neurons in the spinal cord. Sensitization leads not only to lowering of itch sensation but also to attenuated inhibition of itch by pain. Therefore, even such stimuli that normally evoke pain and suppress itch would cause itch. This could explain the vicious itch-scratch cycle observed in patients with atopic dermatitis. Our recent study has shown that inflammatory pain mediators like bradykinin and serotonin also evoke itch in atopic dermatitis, which cannot be suppressed by antihistamines. This implies that anti-inflammatory medications like topical application of corticosteroid should be the most promising anti-pruritic strategy in atopic dermatitis.

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Olopatadine hydrochloride (Olopatadine) is an antiallergic drug with selective histamine H₁ receptor antagonist activity. This study was undertaken to clarify the effects of Olopatadine on CCL17 and CCL22 production by PBMCs from patients with AD during the treatment. We measured the levels of CCL17, CCL22, IFNγ, IL-12 and IL-18 in plasma and the supernatants of cultured PBMCs with or without dust mite allergen extract (DME) in the AD patients before and after treatment with oral Olopatadine (10mg/day) for 4 weeks. The plasma levels of CCL17 and CCL22 significantly decreased after the treatment compared with before the treatment and were significantly correlated with SCORAD index. PBMCs from AD patients taken after the treatment and cultured with DME for 5 days, showed significantly lower levels of CCL17 production than those taken before the treatment and cultured with DME for 5 days. Our data demonstrate that Olopatadine inhibits CCL17 and CCL22 production by PBMCs from AD patients, which are important regulators of Th2 recruitment in the skin.

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Atopic dermatitis is a multifactorial and hereditary cutaneous allergic disease which requires various anti-symptomatic treatments. Therapeutic guidelines indicate standard treatments useful in daily dermatological clinics. The therapeutic mainstay is topical steroid and tacrolimus. Topical tacrolimus not only complement existing treatment options but also overcome some of the drawbacks of topical steroid therapy and fulfil the long-term needs of patients in preventing disease progression. In order to reduce the possible long-term adverse effects and increase the usefulness, it is important to monitor the clinical dose in daily clinics and to create a suitable combination therapy.

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Cyclosporine is effective for atopic dermatitis from the viewpoint of EBM, and has been widely applied in Europe and other countries. A prompt improvement is expected by cyclosporine due to its strong immunity control action. Cyclosporine has a good indication for the patient who is in erythrodermic condition or resistant to topical steroids showing lichenification and prurigo like nodules, or has topical side effect such as skin atrophy, capillary enhance and steroid purpura. Cyclosporine, which has the different action mechanism from steroid, is of great value for the treatment of atopic dermatitis although carefulness is required for long term administration, and it will be necessary to clarify the location of the cyclosporine in the treatment guideline for atopic dermatitis in the future.

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There are currently no effective therapies for severe atopic dermatitis except for the administration of glucocorticoids or immunosuppressants which have several severe side effects. The transfection of cis-element double-stranded oligodeoxynucleotides (ODNs), reffered to as “decoy”, has been reported to be a powerful tool and a new type antigene treatment strategeis for gene therapy and for study gene transfection. Systemic ODNs act as decoy cis-elements to block the binding of nuclear factors to the promoter regions of targeted genes, thus resulting in the inhibition of gene transactivation both in vitro and in vivo. Recently, a targeted disruption of the STAT6 DNA binding activity by a STAT6 decoy has been reported to block IL-4-deriven Th2 cell response in vitro, and reported the inhibitory effect of a STAT6 Decoy ODN on the induction of the IgE medicated late phase reaction in AD mouse model in vivo system, acute and chronic contact hypersensitivity and TNP-IgE-transgenic mice. In this paper, we demonstrated that STAT6 decoy ODN ointment can be effective for patients with AD as a gene therapy in a clinical study.

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