INHIBITION OF EXPRESSION OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II MOLECULES IN MACROPHAGES INFECTED WITH LEISHMANIA-DONOVANI OCCURS AT THE LEVEL OF GENE-TRANSCRIPTION VIA A CYCLIC AMP-INDEPENDENT MECHANISM

Among the important pleiotropic responses to gamma interferon (IFN-gamma) during the activation of macrophages (M-phi) is the increased expression of major histocompatibility complex class II genes. In the present study, infection with Leishmania donovani was shown to inhibit in parallel the induction by IFN-gamma of H-2 A-beta-gene transcription, class II mRNA accumulation, and H-2 A(d) protein expression in cells of the murine macrophage cell line P388D1. Treatment of P388D, cells with either the adenylate cyclase activator cholera toxin or the protein kinase A activator N6-2'-O-dibutyryl cyclic AMP (dibutyryl cAMP) similarly inhibited the induction by IFN-gamma of class II protein expression, and in parallel with Leishmania infection, cholera toxin inhibited the induction of mRNA for the H-2 A-alpha and H-2 A-beta proteins. Concentrations of intracellular cAMP were significantly increased in cholera toxin-treated cells but not in leishmania-infected cells. These findings indicate that at least one mechanism by which Leishmania infection attenuates the activation of M-phi by IFN-gamma involves selective, transcriptional inhibition of major histocompatibility complex class II genes via a cAMP-independent mechanism.