Glyteer, Soybean Tar, Impairs IL-4/Stat6 Signaling in Murine Bone Marrow-Derived Dendritic Cells: The Basis of Its Therapeutic Effect on Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is a common inflammatory skin disease. Recent studies have revealed the involvement of T helper (Th)2 cytokines including Interleukin 4 (IL-4) in the pathogenesis of AD. Since epidermal Langerhans cells (LCs) and dermal myeloid dendritic cells (DCs) produce CCL17 and CCL22 that chemoattract Th2 cells, interfering with CCL17 and CCL22 production from LCs and dermal myeloid DCs may be beneficial in the treatment of AD. To investigate this, we stimulated murine bone marrow-derived DCs (BMDCs) with IL-4. IL-4 stimulation produced Ccl17 and Ccl22, which was attenuated by soybean tar Glyteer, a known aryl hydrocarbon receptor (Ahr) activator. Notably, Glyteer treatment blocked the nuclear translocation of Stat6 induced by IL-4 stimulation, suggesting that this treatment impairs the IL-4/Stat6 signaling pathway in BMDCs. Unexpectedly, Glyteer treatment did not potently upregulate the expression of Cyp1a1, a specific Ahr-responsive gene, suggesting that its inhibitory machinery for Ccl17 and Ccl22 expression is likely to operate in an Ahr-independent manner. These findings indicate that Glyteer may exhibit therapeutic potential for AD by downregulating the CCL17 and CCL22 production from DCs in a Th2-deviated microenvironment.

Pathogenic implication of epidermal scratch injury in psoriasis and atopic dermatitis

“…97,100-102 IL-4 and IL-13 stimulate dendritic cells to produce CCL17 and CCL22, which are potent chemoattractants for Th2 cells, and are sensitive biomarkers for disease severity in AD. 103,104 Although IL-31 is the major pruritogenic cytokine in AD, 105,106 IL-4 and IL-13 also induce pruritus, and augment IL-31-mediated atopic itch. Pruritus-induced scratching is likely to enhance skin inflammation, because the severity of dermatitis is reduced by avoiding mechanical scratching by protective shields, 24 or by injecting antipruritic anti-IL-31 receptor antibody.…”

Genome-Wide Transcriptional Analysis Reveals Novel AhR Targets That Regulate Dendritic Cell Function during Influenza A Virus Infection

“…This is likely not an effect that is unique to the prototype AhR agonist TCDD, as other AhR ligands cause similar changes in T cell responses to IAV infection (37). Also, soybean tar extract, which contains AhR agonists, dampened CCL17 production by mouse bone marrow-derived DCs, although it is not certain that this occurred in an AhR-dependent mechanism (86). Furthermore, exposure to other AhR ligands, such as diesel exhaust particles or tryptophan metabolites, impacts the expression of other chemokines in the CNS or lung-derived cells (71,87,88).…”

“…Very few studies have defined what controls expression of CCL17 during infection. Takemura et al (86) suggest a role for IL-4/STAT6 in driving Ccl17 expression in DCs. Although the mechanism is not yet known, paracrine activation of DCs by other immune cells, such as NKT cells, has also been shown to enhance CCL17 production (70).…”

T helper type 2 signatures in atopic dermatitis

“…79 Dendritic cells, especially Langerhans cells, are one of the major sources of CCL17 and CCL22 production upon IL-4 stimulation. [80][81][82] CCL17 and CCL22 are potent attractants for CCR4-expressing Th2 cells. 83,84 Increased CCL17 is also evident in AD-like mouse models.…”