Suppressor of cytokine signalling (SOCS) proteins are inducible feedback inhibitors of Janus kinase (JAK) and signal transducers and activators of transcription signalling (STAT) pathways. Interferon (IFN)-gamma induces the expression of the socs1 gene in several cell types through several cis elements present in its promoter and their binding proteins. Socs1 expression is induced in the human keratinocytes HaCaT cell line through sequential activation of STAT1 and IRF-1. Comparison of the 5'-upstream sequences of the mouse and human socs1 genes identified conserved binding sites for IRF-1 regulatory elements. Although this response element is able to bind IRF-1 in human cells, no IFN-gamma responsiveness was observed with human socs1 promoter reporter constructs containing this element. In contrast the mouse socs1 promoter was fully responsive. The mouse promoter contains two cis-acting elements which modulate its expression and are recognized by IRF-1 and Sp2. Despite the absence of Sp2 in the 5'-upstream sequence of the human promoter, silencing of Sp2 by RNA interference clearly demonstrated that Sp2 is required for IFN-gamma-induced regulation of socs1 mRNA both in human and mouse.