**8. Prostanoids and Treg induction**

T regulatory cells (Treg) make up one of the T cell subsets which has potent suppressive functions in various disease models. There are several reports that analyzed Treg number and function in AD patients, but those results are not necessarily consistent (Brandt et al., 2009; Ou et al., 2004; Schnopp et al., 2007; Verhagen et al., 2006). However, considering the fact that loss of Treg in skin can lead to AD-like skin lesions in both human (Ochs et al., 2005) and mouse (Brunkow et al., 2001), it is very likely that Treg play important roles in the pathogenesis of AD.

It has been well known that ultraviolet (UV) radiation causes immunosuppression, and it is one of the effective treatment options for AD. Although multiple suppression mechanisms have been proposed, induction of Treg is considered one of the central factors for the suppression mechanism. As blocking of prostanoid production by treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) treatment can abolish the immunosuppressive effect through UV (Chung et al., 1986; Hart et al., 2002; Walterscheid et al., 2002), it has been suspected that prostanoids play important roles in the UV-induced immunosuppression, especially in Treg induction. By UV radiation, various prostanoids are produced in the skin, with PGE2 being the most abundant prostanoids (Kuwamoto et al., 2000; Ruzicka et al., 1983; Soontrapa et al., 2011). Recently, it has been revealed that PGE2-EP4 signaling mediates the induction of Treg by UV irradiation, and regulates UV-induced immunosuppression (Soontrapa et al.). Blockade of EP4 signaling suppresses the increase of Treg in dLNs and abolishes the immunosuppressive effect of UV. Blockade of EP4 signaling also diminishes the RANKL expression on KCs after UV irradiation (Soontrapa et al., 2011). It is known that RANKL expression on UV-irradiated KCs activates LCs, and the RANKL-activated LCs function to induce Treg in dLNs (Loser et al., 2006). These results indicate that PGE2-EP4 signaling regulates RANKL expression on KCs and controls Treg induction from UV.

Other than PGE2, it has been reported that PGD2 induces Treg differentiation through DP in a mouse asthma model (Hammad et al., 2007). Inhalation of a selective DP1 agonist suppressed the cardinal features of asthma by targeting the function of lung DCs. In mice treated with a DP1 agonist or receiving DP1 agonist-treated DCs, there was an increase in Tregs that suppressed inflammation in an IL-10-dependent way (Hammad et al., 2007). These effects of a DP1 agonist on DCs were mediated by cyclic AMP-dependent protein kinase A. Taken together, control of EP4 and/or DP1 signaling could represent a novel immunosuppressive approach.
