Parasite Immunology , 2001: 23: 599±606 In vitro indomethacin administration upregulates interleukin-12 production and polarizes the immune response towards a Th1 type in susceptible BALB/c mice infected with Leishmania mexicana JOSE Â LUIS MARTI Â N PE Â REZ-SANTOS & PATRICIA TALAMA Â S-ROHANA Experimental Pathology Department, CINVESTAV-IPN, Me Âxico DF, Me Âxico SUMMARY The immune response in Leishmania infected BALB/c mice is associated with a Th2 type cellular response, which has been characterized by the absence of interleukin (IL)-12, interferon (IFN)-g, and nitric oxide (NO) and the presence of IL-10 and IL-4. Prostaglandins (PGs) can modulate the immune response inhibiting the development of Th1 response and enhancing the development of Th2 response. We investigated the production of PGs and their effects on cytokine and NO production by spleen cells from Leishma- nia mexicana infected BALB/c and C57BL/6 mice. Increased production of PGs was noted as early as 1 week after infection in BALB/c mice, whereas in infected C57BL/6 mice PGs were not detected. In vitro administra- tion of indomethacin (INDO), a specific inhibitor of PGs synthesis, reduced PGs production at normal levels, and increased IL-12, IFN-g, and NO production in infected BALB/c mice. Whereas, IL-10 and IL-4 were not affected. Moreover, INDO did not modulate cytokine and NO production in infected C57BL/6. INDO addition induced the intracellular killing of parasites in infected BALB/c mice. Together, these results suggest that suppression of PGs by INDO may promote the development of a protective Th1 type response in susceptible mice by a mechanism, which involves an enhancement of IL-12, IFN-g and NO production. These findings were confirmed by smaller lesions in BALB/c mice, when treated with INDO. Keywords indomethacin, Leishmania mexicana, interleukin-12, prostaglandin E 2 , Th1 type immune response INTRODUCTION Human leishmaniasis is initiated by inoculation of proto- zoan parasites of the genus Leishmania into the skin through the bite of infected sandflies. Leishmania sp. are intracellular protozoa that colonize macrophages and their control requires the induction of immune responses capable of activating macrophages to a microbicidal state (1±4). Studies in vitro have clearly shown that the anti-leishmanial effector function is mediated by interferon (IFN)-g. This cytokine is known to induce the synthesis of nitric oxide (NO) synthase by macrophages, which leads to the production of reactive nitrogen radicals, toxic to the parasite (5,6). Several mechanisms, none exclusive, have been described to account for the impairment of immune responses during experimental leishmaniasis in susceptible BALB/c mice: reduced synthesis of interleukin (IL)-12, a cytokine produced primarily by monocytes and macro- phages that stimulates growth of Th1 cells and induces synthesis of IFN-g by these cells (7), and an exuberant amount of macrophage-deactivating factors, such as IL-4, IL-10 and transforming growth factor (TGF)-b that inhibits the anti-leishmanial effector function of IFN-g released by Th1 cells (8±10). Work in several laboratories has revealed that the immune response in Leishmania sp. infected BALB/c mice is characterized by an excessive production of prostaglandins (PGs) that inhibits the lymphoproliferative response (11,12). In addition, it has been shown that Leishmania major infected BALB/c mice treated with q 2001 Blackwell Science Ltd 599 Correspondence: Patricia Talama Âs-Rohana, Experimental Pathology Department, CINVESTAV-IPN, Avenida IPN no. 2508, Col. San Pedro Zacatenco, Me Âxico DF 07360, Me Âxico (e-mail: ptr@mail.cinves- tav.mx). Received: 26 January 2001 Accepted for publication: 10 August 2001