Absent in Melanoma 2 (AIM2) is a member of the HIN-200 family of hematopoietic, IFN-inducible nuclear proteins associated with infection defense and tumor pathology. Recently, AIM2 was found to act as a DNA sensor in innate immunity. In addition, a high frequency of AIM2-alterations was observed in microsatellite unstable tumors. To elucidate AIM2 function in colorectal tumors, we here addressed AIM2-responsive genes by microarray. Among genes up-regulated by AIM2, there were a number of interferon-stimulated genes (ISGs: IFIT1, IFIT2, IFIT3, IFI6, IRF7, ISG15, HLA-DRA, HLA-DRB, TLR3 and CIITA) as well as genes involved in intercellular adhesion and matrix remodeling. Expression of ISGs correlated with expression of AIM2 in ten different IFN- treated colorectal cancer cell lines. Moreover, knock-down of AIM2 resulted in reduced expression of HLA-DRA, HLA-DRB, and CIITA in IFN- treated cells. IFN- independent induction of HLA-DR genes and their encoded proteins was also demonstrated upon transient induction of AIM2. STAT-signaling was not involved in IFN- independent induction of ISGs, arguing against participation of cytokines released in an autocrine manner. Our data indicate that AIM2 mediates IFN- dependent and independent induction of several Interferon stimulated genes (ISGs) including genes encoding the MHC II antigens HLA-DR and .