Background)Microsomal prostaglandin (PG) E synthase-1 (mPGEs-1) is the enzyme responsible for the second step of Prostaglandin E2 (PGE₂). The expression of mPGEs-1 was observed in various contexts, such as inflammation, fever, pain, female reproduction, and cancer growth. Immune cells, especially regulatory T cells (Tregs) related to cancer growth, tissue repair and angiogenesis. It was reported that PGE₂ modulates Tregs cell function and differentiation.Based on these previous reports, we ypothesized mPGEs-1/PGE₂ axis contribute to wound healing and granulation formation by accumulation of Tregs.
Material and Method) Male 6-8 weeks old C57Bl/6N (wild type=WT) mPGES-1 deficient mice (mPGES-1KO) were used. Polyurethane sponge disks were implanted into dorsal subcutaneous tissue of mice. Angiogenesis was estimated by weight of granulation tissue and the expressions of CD31, VEGF and TGF-beta by immunohistochemical analysis and real time PCR. Contribution of Tregs was estimated by immunohistichemical study and real time PCR against FOXp3 specific transcript factor for Tregs. Involvement of Tregs in granulation formation was analyzed by administration of CD25 antibody or folate receptor 4 (FR4) antibody.
Results) Compared to WT, weight of granulation tissue was significantly suppressed in mPGEs-1KO (P<0.05). Expressions of CD31 and VEGF in the granulation tissues were significantly suppressed in mPGEs-1KO. Expression of FOXp3 in the granulation tissue was significantly suppressed in mPGEs-1KO compared to WT (P<0.05). The numbers of accumulated FOXp3 positive cells around granulation tissue were also impaired in mPGEs-1KO compared to WT (P<0.05). In addition, mRNA and protein expression of TGF-beta were significantly decreased in mPGEs-1KO. WT treated with CD25 antibody or FR4 antibody were significantly suppressed granulation formation compared to IgG treated mice but not in mPGEs-1KO.
Conclusion) These results suggested that mPGEs-1/PGE₂ axis induces angiogenesis and granulation formation by accumulating Tregs.