INTRODUCTION
Atopic dermatitis (AD) is one of the most common inflammatory skin disorders. It is present in both the very young and the very old and is a significant cause of decreased quality of life (QOL).1 The pathogenesis of AD is an interplay between impaired barrier function, replacement of commensal bacteria with pathogenic Staphylococcus and Streptococcus species, and disordered production of ceramides.1,2 In inflammatory skin, the pH is alkaline,3,4 and this favors enzymatic conversion of ceramide to sphingosine-1 phosphate (S1P), which is pro-inflammatory.5
Fire ants produce an alkaloid, solenopsin, which has a long lipid side chain. We have synthesized derivatives of solenopsin, and have demonstrated that they have antiangiogenic activity.6 Based upon the structure of solenopsin, we hypothesized that solenopsin analogs would have the biological activity of ceramides without being able to be metabolized to proinflammatory S1P.2,6-9 This turned out to be correct, and topical application of solenopsin analogs demonstrated antiinflammatory activity on a validated murine model of psoriasis.2 Remarkably, the resolution of Th17 mediated inflammation was accompanied by induction of IL-12.2 This suggests that a novel method of resolution of cutaneous inflammation could be induction of Th1 immunity to suppress Th17 immunity. To determine whether this was specific to Th17 immunity, or common to other forms of cutaneous inflammation such as Th2 mediated immunity, we studied the effect on OVA-induced AD.
Both psoriasis and AD demonstrate cutaneous inflammation but are clinically different. Atopic dermatitis is associated with ill-defined erythematous plaques, while psoriatic plaques are well defined, and often less itchy than AD. Psoriasis produces an excess of antimicrobial peptides, while AD produces fewer peptides.10 Atopic dermatitis is associated with genetic decreases in keratinocyte structural proteins,11,12 and tends to appear earlier in life than psoriasis. Finally, AD is mediated by Th2 cytokines such as IL-4 and IL-13, while psoriasis is mediated by IL-17.13,14
Atopic dermatitis and psoriasis also have commonalities as well. They both have increased alkalinity and activation of NF-kappaB transcription.11,15 In addition, they are both angiogenic and have thickened epidermal layers. They are also increased in incidence and severity in patients with advanced HIV disease.16-18 Given that HIV is a deficiency in Th1 immunity, this clinical finding suggests that Th1 mediated inflammation plays a tonic role in mediating Th2 and Th17 mediated inflammation.
Fire ants produce an alkaloid, solenopsin, which has a long lipid side chain. We have synthesized derivatives of solenopsin, and have demonstrated that they have antiangiogenic activity.6 Based upon the structure of solenopsin, we hypothesized that solenopsin analogs would have the biological activity of ceramides without being able to be metabolized to proinflammatory S1P.2,6-9 This turned out to be correct, and topical application of solenopsin analogs demonstrated antiinflammatory activity on a validated murine model of psoriasis.2 Remarkably, the resolution of Th17 mediated inflammation was accompanied by induction of IL-12.2 This suggests that a novel method of resolution of cutaneous inflammation could be induction of Th1 immunity to suppress Th17 immunity. To determine whether this was specific to Th17 immunity, or common to other forms of cutaneous inflammation such as Th2 mediated immunity, we studied the effect on OVA-induced AD.
Both psoriasis and AD demonstrate cutaneous inflammation but are clinically different. Atopic dermatitis is associated with ill-defined erythematous plaques, while psoriatic plaques are well defined, and often less itchy than AD. Psoriasis produces an excess of antimicrobial peptides, while AD produces fewer peptides.10 Atopic dermatitis is associated with genetic decreases in keratinocyte structural proteins,11,12 and tends to appear earlier in life than psoriasis. Finally, AD is mediated by Th2 cytokines such as IL-4 and IL-13, while psoriasis is mediated by IL-17.13,14
Atopic dermatitis and psoriasis also have commonalities as well. They both have increased alkalinity and activation of NF-kappaB transcription.11,15 In addition, they are both angiogenic and have thickened epidermal layers. They are also increased in incidence and severity in patients with advanced HIV disease.16-18 Given that HIV is a deficiency in Th1 immunity, this clinical finding suggests that Th1 mediated inflammation plays a tonic role in mediating Th2 and Th17 mediated inflammation.
