PPARγ as an E3 Ubiquitin-Ligase Impedes Phosphate-Stat6 Stability and Promotes Prostaglandins E 2 -Mediated Inhibition of IgE Production in Asthma.

Increased serum IgE level is one of the features of allergic asthma. It is reported that IgE production can be enhanced by E-prostanoid 2 (EP2) receptor of prostaglandin E-2 (PGE(2)); however, whether E-prostanoid 4 (EP4) receptor (encoded by Ptger4) has a unique or redundant role is still unclear. Here, we demonstrated the mice with B cell-specific deletion of the EP4 receptor (Ptger4(fl/fl) Mb1(cre+/-)) showed their serum levels of IgE were markedly increased. A much more severe airway allergic inflammation was observed in the absence of EP4 signal using the OVA-induced asthma model. Mechanistic studies demonstrated that the transcription levels of AID, GLT epsilon, and PST epsilon in EP4-deficient B cells were found to be significantly increased, implying an enhanced IgE class switch. In addition, we saw higher levels of phosphorylated STAT6, a vital factor for IgE class switch. Biochemical analyses indicated that inhibitory effect of EP4 signal on IgE depended on the activation of the PI3K-AKT pathway. Further downstream, PPAR gamma expression was up-regulated. Independent of its activity as a transcription factor, PPAR gamma here primarily functioned as an E3 ubiquitin-ligase, which bound the phosphorylated STAT6 to initiate its degradation. In support of PPAR gamma as a key mediator downstream of the EP4 signal, PPAR gamma agonist induced the down-regulation of phospho-STAT6, whereas its antagonist was able to rescue the EP4-mediated inhibition of STAT6 activation and IgE production. Thus, our findings highlight a role for the PGE2-EP4-AKT-PPAR gamma-STAT6 signaling in IgE response, highlighting the therapeutic potential of combined application of EP4 and PPAR gamma agonists in asthma.