Microsomal Prostaglandin E Synthase-1 Facilitates an Intercellular Interaction between CD4⁺ T Cells through IL-1β
Takako Takemiya1, Chisen Takeuchi2, Marumi Kawakami3
1Medical Research Institute, Tokyo Women's Medical University, Tokyo 162-8666, Japan. takemiya.takako@twmu.ac.jp.
Abstract:
Microsomal prostaglandin synthetase-1 (mPGES-1) is an inducible terminal enzyme that produces prostaglandin E₂ (PGE₂). In our previous study, we investigated the role of mPGES-1 in the inflammation and demyelination observed in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, using mPGES-1-deficient (mPGES-1) and wild-type (wt) mice. We found that mPGES-1 facilitated inflammation, demyelination, and paralysis and was induced in vascular endothelial cells and macrophages and microglia around inflammatory foci. Here, we investigated the role of interleukin-1β (IL-1β) in the intercellular mechanism stimulated by mPGES-1 in EAE spinal cords in the presence of inflammation. We found that the area invaded by CD4-positive (CD4⁺) T cells was extensive, and that PGE₂ receptors EP1-4 were more induced in activated CD4⁺ T cells of wt mice than in those of mPGES-1 mice. Moreover, IL-1β and IL-1 receptor 1 (IL-1r1) were produced by 65% and 48% of CD4⁺ T cells in wt mice and by 44% and 27% of CD4⁺ T cells in mPGES-1 mice. Furthermore, interleukin-17 (IL-17) was released from the activated CD4⁺ T cells. Therefore, mPGES-1 stimulates an intercellular interaction between CD4⁺ T cells by upregulating the autocrine function of IL-1β in activated CD4⁺ T cells, which release IL-17 to facilitate axonal and myelin damage in EAE mice.
Insights
Microsomal prostaglandin synthetase-1 (mPGES-1) drives inflammation in multiple sclerosis models by enhancing interleukin-1β (IL-1β) signaling in CD4+ T cells, leading to IL-17 release and nerve damage.
Area of Science:
- Neuroimmunology
- Inflammation research
- Prostaglandin biology
Background:
- Microsomal prostaglandin synthetase-1 (mPGES-1) produces prostaglandin E₂ (PGE₂), a key inflammatory mediator.
- Previous studies linked mPGES-1 to inflammation, demyelination, and paralysis in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis.
Purpose of the Study:
- To investigate the role of interleukin-1β (IL-1β) in the intercellular mechanisms involving mPGES-1 in EAE spinal cords.
- To elucidate how mPGES-1 signaling influences CD4+ T cell interactions and subsequent damage in EAE.
Main Methods:
- Comparison of mPGES-1-deficient (mPGES-1) and wild-type (wt) mice in an EAE model.
- Analysis of CD4+ T cell infiltration, prostaglandin E₂ (PGE₂) receptor expression (EP1-4), and cytokine production (IL-1β, IL-1 receptor 1 (IL-1r1), IL-17).
Main Results:
- Extensive CD4+ T cell invasion and increased PGE₂ receptor expression were observed in wt mice compared to mPGES-1 mice.
- Higher percentages of CD4+ T cells produced IL-1β and IL-1r1 in wt mice.
- Activated CD4+ T cells released IL-17, indicating mPGES-1's role in promoting this pathway.
Conclusions:
- mPGES-1 upregulates the autocrine function of IL-1β in activated CD4+ T cells.
- This IL-1β autocrine signaling stimulates CD4+ T cells to release IL-17.
- The mPGES-1-mediated IL-1β/IL-17 axis contributes to axonal and myelin damage in EAE.
