Received for publication June 8, 2004.
Revised July 26, 2004.
Accepted for publication July 27, 2004.

Comparative study of glucocorticoids, cyclosporine A and JTE-607 in mouse septic shock model

Abstract

Actions of glucocorticoids, cyclosporine A and JTE-607 (a proinflammatory cytokine inhibitor that does not inhibit interleukin (IL)-2 or interferon-) were compared in a mouse septic shock model, induced by cecal ligation and puncture (CLP). CLP caused elevation of macrophage inflammatory protein (MIP)-2 in lung, and MIP-2 and IL-6 in plasma and peritoneal fluid reaching a peak 4 to 8 h after CLP. Myeloperoxidase (MPO) activity in lung increased and reached a peak 8 to 12 h after CLP. Acute treatment (subcutaneous injections 1 h before and 2 h after CLP) of mice with JTE-607 and methylprednisolone showed significant inhibition of elevated cytokine levels and MPO activity, plus increased survival rate. Similar treatment with cyclosporine A and prednisolone was ineffective. Chronic treatment (subcutaneous injection for 7 consecutive days before CLP) of mice with JTE-607 also showed an inhibitory effect on cytokine production, MPO activity and mortality. In contrast, chronic treatment with cyclosporine A and prednisolone did not inhibit cytokine production or MPO activity, but rather exacerbated mortality. These results indicate that JTE-607 has protective effect on mouse mortality induced by CLP, correlating with inhibition of proinflammatory cytokines, whereas the immunosuppressants, cyclosporine A and prednisolone do not. This suggests that JTE-607, a multiple cytokine inhibitor that does not cause adverse immunosuppression, is useful for treatment of septic shock.

Key words: CLP, JTE-607, cyclosporine A, cytokine, glucocorticoid, immunosuppression

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