Although the mechanisms underlying the EP
Although the mechanisms underlying the EP4-mediated increase in the frequency of mEPSCs via PGE2 remain unclear, mechanisms similar to those driven by EP2 may be involved because activation of both these receptor subtypes increases the intracellular concentration of cAMP (Nishigaki et al., 1995, Sugimoto and Narumiya, 2007). The EP2-mediated, PGE2-induced increase in glutamate release from the synaptosomes of cortical neurons has been reported to be accomplished by increasing the concentration of cAMP in the synaptosomes (Lin et al., 2014). Thus, presynaptic EP2 activated by PGE2 could increase the intracellular cAMP concentration, resulting in the increased presynaptic release of vesicles that is reflected by the increase in mEPSC frequency. In support of this hypothesis, mEPSC frequency was increased in pyramidal neurons in the medial prefrontal cortex and in Purkinje p38 inhibitor in the cerebellar cortex by forskolin, which is a drug that elevates the intracellular cAMP concentration by activating adenylate cyclase (Chen and Regehr, 1997, Huang and Hsu, 2006).
Glial cells, rather than neurons, seem to be the source of PGE2 that affects the function of GnRH neurons in the POA. Cyclooxygenases (COXs) are limiting enzymes producing PGE2. COX-1, but not COX-2, immunoreactivity has been found around GnRH neurons, and the COX-1 immunoreactivity was localized entirely in microglia (Adachi et al., 2009). Another study has shown the involvement of astrocytes in PGE2-mediated regulation of GnRH neural activity in the POA (Clasadonte et al., 2011). Thus, PGE2 produced by these glial cells may increase the synaptic transmission onto GnRH neurons before the surge in luteinizing hormone.
PGE2 activates GnRH neurons directly via EP2, independent of estrous stage (Clasadonte et al., 2011). The postsynaptic system could regulate basal activity of GnRH neurons in a manner dependent on perineuronal PGE2 concentration. On the other hand, both PGE2 and estrogen concentration may be important for the regulation of synaptic inputs into GnRH neurons, and this system could be involved in the generation of the LH surge.
In conclusion, the present study showed that PGE2 treatment significantly increased the frequency of mEPSCs in GnRH neurons in association with positive feedback from estrogen. This PGE2-mediated effect is likely mediated by EP4. PGE2 may modulate the generation of GnRH release, which induces a surge of luteinizing hormone in vivo.
CD4 T cells differentiate into T1, T2, and T17 cells in response to the specific cytokine milieu present in the microenvironment of inflammation and mediate immune inflammatory responses in respective settings., , , Among these T subsets, T17 cells mediate inflammatory responses in patients with many autoimmune diseases, including multiple sclerosis; inflammatory bowel diseases, such as Crohn disease; psoriasis; and rheumatoid arthritis. The importance of T17 cells in these processes was suggested first in animal models of these diseases, including experimental autoimmune encephalomyelitis, and an IL-23– or imiquimod-induced psoriasis model,, , , , and was validated recently by clinical effectiveness of antibodies targeting IL-23 in patients with psoriasis., , , , Differentiation of T17 cells from naive CD4 T cells is driven by the combined actions of IL-6 and TGF-β1., , , , However, differentiated T17 cells have little capacity to induce autoimmune and inflammatory pathology. It should be noted that these T17 cells exhibit plasticity and could transdifferentiate into other effector T-cell types or even regulatory T cells under certain contexts, such as inflammation or autoimmune disease., , Accumulating evidence suggests that T cell–intrinsic IL-23 signaling not only increases IL-17 production of T17 cells but also plays a crucial role in inducing and stabilizing their pathogenicity., , , , It is known that IL-23 acts on IL-23 receptor (IL-23R) complex composed of IL-23R and IL-12 receptor (IL-12R) β1, activates signal transducer and activator of transcription (STAT) 3, and induces expression of , thus forming the self-amplification loop. The pathophysiologic importance of this IL-23–IL-23R signaling has been indicated by several genomic studies that showed a positive correlation between single nucleotide polymorphisms of genes involved in this pathway, such as , , Janus kinase 2 , and , and a wide range of IL-17–dependent autoimmune diseases., ,