The Atopic Dermatitis-Like Symptoms Induced by MC903 Were Alleviated in JNK1 Knockout Mice

Abstract

Atopic dermatitis (AD) is a common allergic disease, imposing large social and economic burdens worldwide. Atopic dermatitis is characterized by eczematous skin lesions and immunoglobulin E (IgE) hypersecretion. We investigated the role of JNK1 on the development of AD in mice. The vitamin D3 analogue MC903, a psoriasis therapeutic drug, was used to induce AD-like symptoms in wild-type (WT) and JNK1-/- mice. The symptoms of AD were less severe in JNK1-/- mice compared with WT mice. JNK1-/- mice showed less ear thickening and infiltration of eosinophils and mast cells in AD-like lesions than did WT mice when treated with MC903. MC903-treated JNK1-/- mice also showed significantly lower level of serum IgE, which was elevated in MC903-treated WT mice. Splenocytes isolated from MC903-treated WT and JNK1-/- mice were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies. Splenocytes from JNK1-/- mice produced lower levels of T-helper (Th2) cytokines (interleukin-4 and -13) and transcription factor GATA-binding protein 3, and produced increased levels of the Th1 cytokines interferon-γ and transcription factor T-box expressed in T cells. Our results indicate that JNK1 plays an important role in the pathogenesis of AD and may be a useful target for therapies to ameliorate AD.

Experimental atopic dermatitis depends on IL-33R signaling via MyD88 in dendritic cells

“…19, 20, 21 In order to understand the function of IL-1 family cytokines in the pathogenesis of AD, we used MC903 to induce AD in mice. First, we investigated the expression of the different IL-1 members in MC903-induced AD and then compared the severity of AD inflammation in BL6 and in gene-deficient mice including IL-1 αβ −/− , IL-1R1 −/− , IL-36 R −/− , IL-36Ra −/− , IL-33 −/− , IL-33 receptor ST2 −/− , MyD88 −/− , DC-specific MyD88 −/− (CD11c-cre × MyD88-floxed) and T-cell-specific MyD88 −/− (CD4-cre × MyD88-floxed) mice.…”

Mast Cells Limit Ear Swelling Independently of the Chymase Mouse Mast Cell Protease 4 in an MC903-Induced Atopic Dermatitis-Like Mouse Model

“…Thus, the potential role of chymase/mMCP-4 in the regulation, via degradation or activation, of TNF-α and other cytokines induced in the MC903-induced AD-like mouse model (Figure 5) would be interesting to follow up. Furthermore, previous studies showed that MC903 treatment promotes a Th2 immune response with significantly increased levels of IgE [27,38], levels which however seems to be independent on c-kit signaling [33,39,40].…”

NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

“…[24][25][26] As shown in Figure 1a and e-h and the left-most panel of Figure 1d, topical administration of MC903 on the ears for 14 days induced tissue swelling, epidermal thickening, and the infiltration of eosinophils and basophils into the dermal layer. Strikingly, topical application of the NOD2/TLR2 ligands together with the AD-inducing agent MC903 further deteriorated the AD-like symptoms, including enhanced ear swelling (Figure 1a-c), more extensive epidermal thickening (Figure 1d and e), and the presence of a larger number of eosinophils in the dermal layer ( Figure 1g).…”

“…[24][25][26] A total of 2 nmol of MC903 (Sigma-Aldrich Corp, St. Louis, MO, USA), which is a Th2-related AD-like skin inflammation-inducing compound, was topically applied in 5 mL of ethanol to the ears of the mice every other day for 14 days (days 0-14, eight times in total). [24][25][26] Ear thickness was measured using a dial thickness gauge (Model G, Peacock, OZAKI MFG. CO., LTD, Tokyo, Japan) and recorded every other day for 16 days.…”