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

Microsomal prostaglandin (PG) E synthase-1 (mPGES-1) and prostacyclin (PGI) synthase (PGIS) are PG terminal synthases that work downstream of cyclooxygenase and synthesize PGE and PGI, 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 PGE levels in DNFB-treated ear tissue was reduced in mPGES-1 KO mice, and that 6-keto PGF (a stable metabolite of PGI) 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 PGE and PGIS-derived PGI might coordinately promote acquired cutaneous immune responses.