Coordinated action of microsomal prostaglandin E synthase-1 and prostacyclin synthase on contact hypersensitivity

Microsomal prostaglandin (PG) E synthase-1 (mPGES-1) and prostacyclin (PGI₂) synthase (PGIS) are PG terminal synthases that work downstream of cyclooxygenase and synthesize PGE₂ and PGI₂, respectively. Although the involvement of PG receptors in acquired cutaneous immune responses was recently shown, the roles of these PG terminal synthases remain unclear. To identify the pathophysiological roles of mPGES-1 and PGIS in cutaneous immune systems, we applied contact hypersensitivity (CHS) to mPGES-1 and PGIS knockout (KO) mice as a model of acquired immune responses. Mice were treated with 1-fluoro-2,4-dinitrobenzene (DNFB) and evaluated for ear thickness and histopathological features. The results showed that the severity of ear swelling in both gene-deficient mice was much lower than that in wild-type (WT) mice. Histological examination of DNFB-treated ears showed that inflammatory cell infiltration and edema in the dermis were also less apparent in both genotypic mice. LC-MS analysis further showed that the increment in PGE₂ levels in DNFB-treated ear tissue was reduced in mPGES-1 KO mice, and that 6-keto PGF_1α (a stable metabolite of PGI₂) was not detected in PGIS KO mice. Furthermore, we made bone marrow (BM) chimera and found that transplantation of WT mouse-derived BM cells restored the impaired CHS response in mPGES-1 KO mice but did not restore the response in PGIS KO mice. These results indicated that mPGES-1 in BM-derived cells and PGIS in non-BM-derived cells might play critical roles in DNFB-induced CHS. mPGES-1-derived PGE₂ and PGIS-derived PGI₂ might coordinately promote acquired cutaneous immune responses.