We conclude that by specifically knocking CIITA-PIV mRNA down in an in vitro model of non-professional APCs we achieved a level of MHCII gene downregulation reminiscent of that obtained by the IFNα treatment. Several studies show that treating melanoma patients with IFNα results in prolonged disease Selleck CB-839 free survival, although the mechanism of this cytokine remains speculative [54]. Besides its effects on the host immune cells and its antiangiogenic properties, the antitumor action of

IFNα treatment depends on the direct antiproliferative and proapoptotic characteristics of IFNα on the cancer cells [33]. Interestingly, Rigosertib datasheet MHCII-positive melanoma cells that behave as non-professional APCs exhibit a different response to IFNα-induced Jak-STAT signaling compared to immune cells (i.e., professional APCs) [33]. This fact, coupled with our data indicating the opposing effect of IFNα on MHCII expression in non-professional vs. professional APCs [6], suggested that a further definition of the mechanism responsible for the IFNα-mediated downregulation of MHCII expression in non-professional APCs was needed. The role IFNs as modulators of MHCII gene expression has been studied in a variety

of systems. It is well established that IFNγ induction of MHCII gene expression operates at the transcriptional level by upregulating the expression of the CIITA gene. Induction is accomplished mostly through the activation of CIITA-IV promoter [4,55], but also by way of less well characterized

mechanisms of activation of CIITA-PI and CIITA-PIII promoters [46,[56], [57] and [58]]. Studies with STAT2 knockout mice have demonstrated that IFNα modulates MHCII expression differently in different cell types through the CIITA-PIV promoter [35,59]. We have previously described that IFNα downregulates the PIV-driven expression Fludarabine mouse of CIITA in human non-professional APCs associated with pancreatic islets cultured ex vivo [ 6]. The opposite, upregulatory effect on MHCII expression that we observed in professional APCs was mostly due to IFNα-mediated persistent activation of CIITA-PIII and CIITA-PI isoforms, respectively, in B lymphoblastoma cell lines and DCs, along with the moderate activation of CIITA-PIV in both cell types. Indeed, MHCII-mediated antigen presentation by professional APCs is not affected in CIITA-PIV knockout mice [ 27]. CIITA-PIII and PIV promoters are constitutively active in some melanoma and glioma cells [9,10,42].