Cytokine Milieu of Atopic Dermatitis, as Compared to Psoriasis, Skin Prevents Induction of Innate Immune Response Genes

Abstract

Atopic dermatitis (AD) and psoriasis are the two most common chronic skin diseases. However patients with AD, but not psoriasis, suffer from frequent skin infections. To understand the molecular basis for this phenomenon, skin biopsies from AD and psoriasis patients were analyzed using GeneChip microarrays. The expression of innate immune response genes, human β defensin (HBD)-2, IL-8, and inducible NO synthetase (iNOS) was found to be decreased in AD, as compared with psoriasis, skin (HBD-2, p = 0.00021; IL-8, p = 0.044; iNOS, p = 0.016). Decreased expression of the novel antimicrobial peptide, HBD-3, was demonstrated at the mRNA level by real-time PCR (p = 0.0002) and at the protein level by immunohistochemistry (p = 0.0005). By real-time PCR, our data confirmed that AD, as compared with psoriasis, is associated with elevated skin production of Th2 cytokines and low levels of proinflammatory cytokines such as TNF-α, IFN-γ, and IL-1β. Because HBD-2, IL-8, and iNOS are known to be inhibited by Th2 cytokines, we examined the effects of IL-4 and IL-13 on HBD-3 expression in keratinocyte culture in vitro. We found that IL-13 and IL-4 inhibited TNF-α- and IFN-γ-induced HBD-3 production. These studies indicate that decreased expression of a constellation of antimicrobial genes occurs as the result of local up-regulation of Th2 cytokines and the lack of elevated amounts of TNF-α and IFN-γ under inflammatory conditions in AD skin. These observations could explain the increased susceptibility of AD skin to microorganisms, and suggest a new fundamental rule that may explain the mechanism for frequent infection in other Th2 cytokine-mediated diseases.

National Psoriasis Foundation clinical consensus on psoriasis comorbidities and recommendations for screening

“…65 This finding has been related to a cytokine profile in psoriatic plaques that upregulates anti-bacterial proteins in keratinocytes. 66 One series from Germany suggests that the rate of cutaneous infection in psoriatics is diminished when compared to a control population. 42 This may not be the case for infections of the respiratory tract.…”

Cathelicidin deficiency predisposes to eczema herpeticum

“…Real-time RT-PCR was performed using an ABI 7000 Sequence Detection system (Applied Biosystems, Foster City, CA) as previously described. 4 Human GAPDH and rodent GAPDH were purchased from Applied Biosystems. Primer and probe sequences for cathelicidin were designed as previously described.…”

“…It has been postulated that this may explain susceptibility of these individuals to recurrent bacterial skin infections. 3,4 Eczema herpeticum (ADEH) is a disseminated herpes simplex virus (HSV)-1 or -2 infection that occurs in a subset of patients with AD. 5,6 Left un-treated, ADEH may be fatal due to systemic viremia.…”

IL‐12, IL‐23, and IL‐27 enhance human β‐defensin‐2 production in human keratinocytes

“…In cutaneous infection or inflammatory diseases like psoriasis, hBD-2 production in epidermal keratinocytes is enhanced [7,32]. In these situations, APC such as DC, macrophages, and Langerhans cells are activated and these produce large amounts of IL-12, IL-23, and IL-27 in addition to the pro-inflammatory cytokine IL-1b [11,33].…”

“…Cell differentiation was induced by incubating with KBM containing a high calcium concentration (1.25 mM) for 48 h because hBD-2 production is enhanced in differentiated keratinocytes [32]. The cells were incubated with 10 ng/mL IL-1b and/ or the indicated concentrations of IL-12, IL-23, or IL-27 in highcalcium KBM for 48 h. The hBD-2 concentration of the culture supernatants was measured using ELISA (Peprotech, Rocky Hill, NJ).…”