Involvement of prostaglandin E2 released from leptomeningreal cells in increased expression of transforming growth factor-β in glial cells and cortical neurons during systemic inflammation

The leptomeninges play a central role in the antiinflammatory response through the glia-neuron interaction during systemic inflammation. In the present study, we examined the possible production of two potent antiinflammatory mediators, prostaglandin E-2 (PGE(2)) and transforming growth factor-beta 1 (TGF-beta 1) by leptomeningeal cells during systemic inflammation. After immunization with the complete Freund's adjuvant (CFA), cyclooxygenase (COX)-2 and membrane-bound PGE synthase-1 (mPGES-1) were induced in the leptomeninges. Primary cultured leptomeningeal cells secreted PGE(2) after treatment with lipopolysaccharide (LPS) or proinflammatory cytokines. The LPS-induced release of PGE2 was depressed by a selective COX-2 inhibitor, NS-398. On the other hand, TGF-beta 1 and TGF-beta receptor II (TGF-beta RII) both markedly increased in the leptomeninges and the parenchymal cells after the CFA injection. Double-staining immunohistochemistry demonstrated TGF-beta 1 to be induced in both glial cells and cortical neurons, whereas TGF-beta RII was induced only in cortical neurons. Furthermore, the conditioned medium prepared from the leptomeningeal cells after LPS stimulation was able to induce an increased expression of TGF-beta 1 and TGF-beta RII in the primary cultured glial cells and cortical neurons. This increased expression was suppressed by NS-398. PGE(2) was found to increase directly the production of TGF-beta 1 and TGF-beta RII in the primary cultured cells. These observations strongly suggest that PGE(2), which is biosynthesized by the leptomeninges, mainly regulates the production of TGF-beta 1 by glial cells and cortical neuron, thus playing a protective role in the cortical neurons during systemic inflammation. Furthermore, TGF-beta 1 may also exert a protective effect directly on the cortical neurons. (c) 2006 Wiley-Liss, Inc.