35 Increased Th2 Activity in vivo Promotes the Development of Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease that predisposes towards the development of subsequent atopic phenotypes. The pathogenesis of AD is still poorly understood and likely is due to defects in skin and immune function. In the present study we focus on how Th2 development promotes atopic dermatitis. It is well documented that Stat6 plays a pivotal role in the activation of Th2 cytokines including IL-4 and IL-13. Recent studies from our laboratory have shown that transgenic mice expressing active Stat6 (Stat6VT) in T cells have increased Th2 differentiation in vivo and in vitro. All Stat6VT transgenic mice developed severe blephritis (inflammation around the eye) characteristic of IL-4 over-expressing mice. Furthermore, 30-50% of the Stat6VT transgenic mice developed the characteristic symptoms of atopic dermatitis involving erythema and inflammation of different organs such as ears, nose, face, neck and tail. Histological analyses of tissue samples from mouse ears of Stat6VT transgenic mice revealed dermal infiltration of lymphocytes and eosinophils, whereas neutrophils appeared prominent in more severe lesions. This may reflect a skewing of Th2 to Th1 inflammation in more chronic lesions. To define the importance of IL-4 in these phenotypes, we mated Stat6VT transgenic and IL-4-deficient mice (Stat6VT/IL-4−/−). T cells from Stat6VT/IL-4−/− mice were still capable of becoming Th2-like cells, secreting IL-5 and IL-13. However, blephritis in Stat6VT/IL-4−/− mice occurred less frequently and with only mild symptoms. Stat6VT/IL-4−/− mice did not develop atopic dermatitis. These results suggest that, in contrast to the role of IL-13 in asthma, IL-4 is an effector cytokine in these allergic conditions.