¹Preclinical Pharmacology, Johnson and Johnson Skin Research Center, CPPW, a unit of Johnson & Johnson Consumer Companies, Inc., Skillman, New Jersey, USA

Correspondence: Dr Michael D. Southall, Preclinical Pharmacology, Johnson & Johnson, 199 Grandview Road, Skillman, New Jersey 08558, USA. E-mail: msoutha@cpcus.jnj.com

Received 15 January 2007; Revised 9 April 2007; Accepted 31 May 2007; Published online 19 July 2007.

Abstract

Sertaconazole nitrate is an antifungal agent that exhibits anti-inflammatory activity; however, the mechanism for this action was unknown. We investigated the cellular mechanisms by which sertaconazole exerts its anti-inflammatory activity in keratinocytes and human peripheral blood mononuclear cells (PBMCs). Paradoxically, sertaconazole was found to activate the proinflammatory p38 mitogen-activated protein kinase. Treatment with sertaconazole also resulted in the induction of cyclooxygenase-2 (COX-2) and the subsequent release of prostaglandin E₂ (PGE₂). Knocking down p38 in keratinocytes using small interfering RNA resulted in an inhibition of sertaconazole-induced PGE₂ release confirming that activation of p38 was required for PGE₂ production. Additionally, in stimulated keratinocytes and human PBMCs, sertaconazole was found to suppress the release of cytokines. Treatment with anti-PGE₂ antiserum or the COX-2 inhibitor NS398 reversed the inhibitory effects of sertaconazole on the release of proinflammatory cytokines, linking endogenous PGE₂ with the anti-inflammatory effects. Finally, in an in vivo mouse model of tetradecanoyl phorbol acetate (TPA)-induced dermatitis, the sertaconazole-mediated inhibition of TPA-induced ear edema was reversed by NS398. Biochemical analysis of tissue biopsies revealed increase in PGE₂ levels in sertaconazole-treated mice. Thus, activation of the p38–COX-2–PGE₂ pathway by agents such as sertaconazole provides anti-inflammatory therapeutic benefits.