*3.2. CD4+ Th2 Cells*

Naïve CD4+ T cell differentiation into the Th2 subset is implicated as a key driver of allergen-induced inflammatory diseases such as asthma, and multiple studies reveal that prostacyclin inhibits Th2 inflammation [24]. For instance, IP KO mice sensitized and challenged with an extract of the ubiquitous aeroallergen *Alternaria* had significantly greater numbers of IL-5+ and IL-13+ CD4+ T cells compared to WT mice, further solidifying that endogenous IP signaling is a critical restraining influence on CD4+ Th2 cell differentiation [24]. While IL-4 is recognized as an important cytokine in differentiating CD4+ T cells down the Th2 pathway, IL-33 also has this effect. Cicaprost dose-dependently decreased IL-33-induced production of IL-4, IL-5, and IL-13 by CD4+ cells from WT mice but not in IP KO CD4+ T cells [24]. Cicaprost's inability to suppress Th2 cytokine production in CD4+ Th2 cells from the IP KO mice confirmed the specificity of its effect on the prostacyclin-IP signaling pathway. Additionally, cicaprost decreased the IL-33-induced CD4+ Th2 cell production of IL-2 [24]. Prostacyclin reducing IL-2 could explain the decreased activation of the Th2 cells and their reduction in IL-5 and IL-13 production.

Signal Transducer and Activator of Transcription (STAT) 6 is a transcription factor that is activated by IL-4 and IL-13 and is critical for Th2 cell differentiation [25]. Indomethacin is a COX inhibitor that increases allergic proinflammatory cytokine responses in a STAT6-independent fashion [25]. Indomethacin administration likely resulted in increased allergic inflammation as a result of its decreasing prostacyclin production [25]. This was confirmed by a study using WT, STAT6 KO, IP KO, and IP-STAT6 double knock-out (DKO) mice. In this in vivo study in which ovalbumin was used to sensitize and challenge mice, IP KO mice had greater allergic lung inflammation compared to WT mice. STAT6 KO mice had undetectable levels of Th2 cytokines, while IP-STAT6 DKO mice also had significantly increased IL-5, IL-13, IL-1α, and IL-β protein expression compared to STAT6 KO mice [25]. This revealed that endogenous IP signaling inhibits a STAT6-independent pathway that can drive allergic inflammation [25].
